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Food and Chemical Toxicology 68 (2014) 154–182

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Food and Chemical Toxicology

journal homepage: www.elsevier .com/locate/ foodchemtox

Invited Review

The effects of bioactive compounds from plant foods on mitochondrialfunction: A focus on apoptotic mechanisms

http://dx.doi.org/10.1016/j.fct.2014.03.0170278-6915/� 2014 Elsevier Ltd. All rights reserved.

Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; AIF, apoptosis-inducing factor; AMPK, AMP-activated protein kinase; ANT, adenine nutranslocase; Apaf-1, apoptotic protease activating factor-1; ATP, adenosine triphosphate; ATP-ase, ATP synthase; AZT, azidothymidine; BH, Bcl-2 homology; CA, cafCACT, carnitine/acylcarnitine translocase; CAD, caspase-activated DNase; CAPE, caffeic acid phenetyl ester; CAT, catalase; cIAP, cellular inhibitor of apoptosis procardiolipin; COX, cyt c oxidase; CPT, carnitine palmitoyl transferase system; CPT1, carnitine palmitoyl transferase 1; CPT2, carnitine palmitoyl transferase 2; CREresponse element; CSA, cyclosporin A; Cy, cyanidin; Cy3G, cyanidin-3-glucoside; cyt c, cytochrome c; DHA, docosahexaenoic acid; DIABLO, direct IAP-binding protlow pI; DISC, death inducing signaling complex; DOX, doxorubicin; Dp, delphinidin; Dp3G, delphinidin-3-glucoside; EA, ellagic acid; EGC, epigallocatechinepigallocatechingallate; Endo G, endonuclease G; EPA, eicosapentaenoic acid; ERKs, extracelular signal-regulated kinases; ETC, electron transport chain; Exe, eexercise; FADD, Fas-associated death domain; FasL, Fas ligand; FOXO3, Forkhead box O3; GCL, c-glutamyl-cysteinyl-ligase; GPX, glutathione peroxidase; GSH, gluGSPE, grape seed procyanidin extract; GSPs, grape seed proanthocyanidins; GSSG, glutathione disulfide; H2O2, hydrogen peroxide; HepG2, hepatocellular carcinoHKs, hexokinase; HO-1, heme-oxygenase-1; HT, hydroxytyrosol; IAP, inhibitors of apoptosis proteins; IkB, inhibitors of NF-kB; IL, interleukin; IMM, inner mitocmembrane; IMS, intermembrane space; JNKs, c-Jun N-terminal kinases; MAPKs, mitogen activated protein kinases; Mcl-1, myeloid leukemia cell differentiationMMP, mitochondria membrane permeabilization; MnSOD, manganese superoxide dismutase; MPTP, mitochondrial permeability transition pore; mRNA, messenmtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; mtROS, mitochondrial ROS; MUFAs, monoinsatured fatty acids; Mv, malvidin; Mv3G, maglucoside; n-3/6 PUFAs, n-3/n-6 polyinsaturated fatty acids; NF-kB, nuclear factor kB; NO, nitric oxide; NQO-1, NADPH-quinone oxidoreductase I; NRF1 and NRF2respiratory factors 1 and 2; Nrf2, nuclear factor-E2-related factor 2; O2

��, superoxide radical; OGD, oxygen–glucose deprivation; OMM, outer mitochondrial meONOO�, peroxynitrite; OO, olive oil; OPP, ortho-phenylphenol; OXLDL, oxidized low density lipoproteins; OXPHOS, oxidative phosphorylation; p38 MAPK, p38activated protein kinase; PA, roanthocyanidin; PARP, poly (ADP-ribose) polymerase; PBR, peripheral benzodiazepine receptor; PDH, pyruvate dehydrogenpelargonidin; Pg3G, pelargonidin-3-glucoside; PGC-1a, peroxisome proliferator-activated receptors coactivator 1a; PI3K, phosphatidylinositol 3-kinase; PKB or AKTkinase B; POPAs, purificated oligomeric proanthocyanidines; PPARs, peroxisome proliferator-activated receptors; RCR, respiratory control ratio; RNS, reactive nspecies; ROS, reactive oxygen species; RV, resveratrol; SAPKs, stress-activated protein kinases; SIRT1, sirtuin 1; Smac, second mitochondria-derived activator of caspsafflower oil; SOD, superoxide dismutase; tBid, truncated Bid; TCA, tricarboxylic acid cycle; TCC, tricarboxylate carrier; TF, theaflavins; TFAM, mitochondrial tranfactor A; TFB2, mitochondrial transcription factor B2; TNF, tumor necrosis factor; TNF-R, tumor necrosis factor receptors; TNF-a, tumor necrosis factor a; TR, theaUCP, uncoupling proteins; VDAC, voltage dependent anion channel; XIAP, X-linked inhibitor of apoptosis protein; YY1, ying yang 1 transcription factor; a-LNA, a-acid; a-TOS, a-tocopheryl succinate; DWm, mitochondrial membrane potential.⇑ Corresponding authors. Address: Università Politecnica delle Marche, Via Brecce Bianche 10, 60131 Ancona, Italy. Tel.: +39 071 2204136 (F. Giampieri). Address: F

Medicina, Università Politecnica delle Marche, Via Ranieri 65, 60100 Ancona, Italy. Tel.: +39 071 2204646; fax: +39 071 2204123 (M. Battino).E-mail addresses: [email protected] (F. Giampieri), [email protected] (M. Battino).

Tamara Y. Forbes-Hernández a, Francesca Giampieri b,⇑, Massimiliano Gasparrini a, Luca Mazzoni a,José L. Quiles c, José M. Alvarez-Suarez a,b, Maurizio Battino a,⇑a Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche, Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, Italyb Dipartimento di Scienze Agrarie, Alimentari ed Ambientali, Università Politecnica delle Marche, Italyc Department of Physiology, Institute of Nutrition and Food Technology ‘‘José Mataix’’, Biomedical Research Center, University of Granada, Spain

a r t i c l e i n f o

Article history:Received 16 December 2013Accepted 14 March 2014Available online 26 March 2014

Keywords:Mitocondrial functionalityApoptosisDietary bioactive compoundsOxidative stress

a b s t r a c t

Mitochondria are essential organelles for cellular integrity and functionality maintenance and theirimparement is implicated in the development of a wide range of diseases, including metabolic, cardiovas-cular, degenerative and hyperproliferative pathologies. The identification of different compounds able tointeract with mitochondria for therapeutic purposes is currently becoming of primary importance.Indeed, it is well known that foods, particularly those of vegetable origin, present several constituentswith beneficial effects on health. This review summarizes and updates the most recent findings concern-ing the mechanisms through which different dietary compounds from plant foods affect mitochondriafunctionality in healthy and pathological in vitro and in vivo models, paying particular attention to thepathways involved in mitochondrial biogenesis and apoptosis.

� 2014 Elsevier Ltd. All rights reserved.

cleotidefeic acid;tein; CL,B, cAMPein with; EGCG,xcessive

tathione;ma cells;hondrialprotein;

ger RNA;lvidin-3-, nuclearmbrane;

mitogen-ase; Pg,, proteinitrongenases; SO,scriptionrubigins;linolenic

acoltà di

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T.Y. Forbes-Hernández et al. / Food and Chemical Toxicology 68 (2014) 154–182 155

Contents

1. The mitochondrial kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
1.1. Mitochondrial structure and functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
1.1.1. Outer mitochondrial membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551.1.2. Inner mitochondrial membrane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

1.2. Mitochondrial biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1571.3. Mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

1.3.1. Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1581.3.2. Mechanisms of apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

2. Effects of dietary compounds on mitochondrial functionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
2.1. Dietary fats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642.2. Vitamins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.2.1. Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1652.2.2. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

2.3. Polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
2.3.1. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.3.2. Phenolic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.3.3. Phenolic alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732.3.4. Stilbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732.3.5. Lignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
3. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Transparency Document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

1. The mitochondrial kingdom

Mitochondria are the cell main energy producers and are there-fore essential for normal cellular functions, including intracellularmetabolic activities and signal transduction of various cellularpathways. The predominant physiological function of mitochon-dria is the generation of adenosine triphosphate (ATP) by oxidativephosphorylation (OXPHOS), but additional functions include thegeneration and the detoxification of reactive oxygen species(ROS), the involvement in some forms of apoptosis, the regulationof cytoplasmic and mitochondrial matrix calcium, the synthesisand the catabolism of metabolites and the transport of the organ-elles themselves to correct locations within the cell (Camara et al.,2010; Brand and Nicholls, 2011). A variety of these mechanismsregulated by mitochondria are strongly implicated in the controlof cellular redox potential, which indicates just how oxidizingthe environment inside the cell is. Cellular redox potential is criti-cally important for normal physiological processes and its dysreg-ulation is implicated in the initiation and proliferation of severaldiseases (Mallikarjun et al., 2012).

Several pathologies apparently related to mitochondria havebeen identified, including metabolic (e.g., type 2 diabetes), cardio-vascular and neurodegenerative diseases, cancer, psychiatric disor-ders and aging (Camara et al., 2010; Frantz and Wipf, 2010).

A complete understanding of mitochondrial function in normaland pathological states is critical for developing the full therapeu-tic potential of the organelle in mitigating or preventing a givendisease. Mitochondrial related diseases are extensively different,and the numerous aspects linking mitochondria to different dis-ease states are still being studied (Camara et al., 2010).

1.1. Mitochondrial structure and functions

The elaborate structure of mitochondria is important for thenormal performance of the organelle and, therefore, constitutes apotential therapeutic target. It is comprised of four distinct com-partments that carry out specialized functions: the outer mito-

chondrial membrane (OMM), the intermembrane space (IMS),the inner mitochondrial membrane (IMM), and the mitochondrialmatrix (Frantz and Wipf, 2010; Camara et al., 2010).

1.1.1. Outer mitochondrial membraneThe OMM borders the narrow IMS and contains many channels

formed by the protein porin that makes the membrane relativelypermeable. The constituents inside the OMM include the periphe-ral benzodiazepine receptor (PBR), the voltage dependent anionchannel (VDAC), other translocated proteins such as hexokinases(HKs), the Bcl family of proteins, such as Bax and Bak (Camaraet al., 2010) and the translocase of the outer membrane (TOM com-plex) (Künkele et al., 1998; Becker et al., 2005).

PBR is a small evolutionarily conserved protein involved in cho-lesterol transport and steroid synthesis. It is also concerned withOMM permeabilization by interaction with the pro-apoptotic Bclfamily proteins and it is found to be in close association with theVDAC. VDAC is a mitochondrial protein synthesized by the nucleargenome and is the principal site for exchange of metabolites, suchas ATP, between the IMS and the cytosol (Okada et al., 2004). As aprincipal portal in and out of the mitochondrion, VDAC mediates aclose dichotomy between metabolism and death in all type of cells(Lemasters and Holmuhamedov, 2006; Camara et al., 2010). AlsoHKs exert a crucial role in promoting cell survival. In particular,HK I and II mediate cytoprotection by binding specifically to theVDAC, in part via the hydrophobic N terminus specific residuesof VDAC in the presence of Mg2+. In tumor cells this association be-tween HK and VDAC provides extra protection against permeabili-zation of the OMM and resistance to apoptosis (Camara et al.,2010). During the activation of cell death programs, permeationof the OMM takes place also through the activation of Bax andBak proteins, which are located in cytosol and translocate to theOMM as a consequence of oxidative stress. In this way, the re-stricted permeability of the OMM protects against cell damageand cell death due to oxidative stress (Camara et al., 2010).

The TOM complex involves the protein-conducting channelTom40, which is its central component, the receptor proteins

156 T.Y. Forbes-Hernández et al. / Food and Chemical Toxicology 68 (2014) 154–182

Tom20, Tom22 and Tom70, and three small Tom proteins, Tom5,Tom6 and Tom7 (Künkele et al., 1998; Koehler et al., 1999; Dem-bowski et al., 2001; Pfanner et al., 2004; Suzuki et al., 2004; Beckeret al., 2005). It mediates the recognition of the nuclear-encodedpreproteins into mitochondria, their transfer through the OMMand the insertion of resident outer membrane proteins (Künkeleet al., 1998; Pfanner et al., 2004).

1.1.2. Inner mitochondrial membraneWhile the OMM is relatively permeable due to the abundance of

VDAC protein, the IMM is highly impermeable, acts as a rigid bar-rier and permits only certain small molecules to pass through(Frantz and Wipf, 2010; Camara et al., 2010). Cation permeationis regulated by ion channels and exchangers whose functions aregoverned by a high IMM potential (Camara et al., 2010).

IMM is involved in a large numbers of pleats called cristae,which contain the protein complexes of the electron transportchain (ETC) and F1F0-ATPase, controlling the fundamental rates ofcellular metabolism. It is also rich in the unusual phospholipid car-diolipin (CL), and maintains a strong negative internal potential of�180 mV required for the ETC function. Since cationic moleculesare attracted to and accumulate preferentially within the nega-tively charged mitochondrial matrix, several strategies take intoconsideration this remarkable property of IMM for targeting mito-chondria in treatment or prevention of many diseases (Frantz andWipf, 2010).

1.1.2.1. Electron transport chain and oxidative phosphorylation. Mito-chondrial ETC consists in a series of redox reactions in which elec-trons are transferred from donors to acceptor molecules, resultingin a trans-membrane proton translocation which drives the forma-tion of an electrochemical gradient. ETC comprises the electrontransport complexes I (NADH dehydrogenase), III (cytochromebc1 complex) and IV (cytochrome c oxidase (COX)) that constituteits actual energy-conserving centers and complex II (succinatedehydrogenase), glycerol phosphate dehydrogenase, ubiquinoneand cytochrome c (cyt c) which are also essential ETC constituents

Fig. 1. Basic mitochondrial structure and function. The figure shows the essential struccatabolic pathways such as FAO, TCA cycle, Mal-Asp and aGP-DhAP shuttles. Ca2+ is takenthe microdomain with the ER. See text for details. (Abbreviations: CU, calcium uniporteFAO, fatty acid oxidation; IMM, inner mitochondrial membrane; IMS, intermembranmitochondrial membrane; TCA, tricarboxylic acid cycle; aGP-DhAP, glycerol 3-phosphat

having critical roles in ETC function and efficiency (Battino et al.,1990; Lenaz et al., 1990; Rauchová et al., 1992).

In mitochondrial ETC, electrons released (i) by the oxidation ofNADH, proceeding from different catabolic pathways, are trans-ferred to complex I, and (ii) by the oxidation of FADH2 or succinateare transferred to complex II. In a series of redox reactions, elec-trons flow to ubiquinone, complex III, cyt c and complex IV, havingoxygen as the final acceptor, which is reduced to water (Pieczenikand Neustadt, 2007; de Moura et al., 2010).

The energy released by electrons while they pass through theETC is used to pump protons from the mitochondrial matrix intothe IMS, creating an electrochemical proton gradient across theIMM, that is essential to mitochondrial bioenergetics: it is com-posed of the pH gradient (DpH) and the mitochondrial membranepotential (DWm) (Brand and Nicholls, 2011). This electrochemicalproton gradient permits ATP synthase (ATP-ase) to use the flow ofH+ through the enzyme back into the matrix to generate ATPfrom adenosine diphosphate (ADP) and inorganic phosphate. Thecomplete process is called OXPHOS. Fig. 1 provides a summaryscheme of mitochondrial structure and function.

1.1.2.2. Mitochondrial reactive oxygen and nitrogen species production(ROS and RNS). ATP production by the OXPHOS process requires acontinuous flow of electrons from which a small percentage do notcomplete the whole series of reactions and directly react with oxy-gen, resulting in the formation of several ROS as secondary ETCproducts (Frantz and Wipf, 2010).

During normal OXPHOS 0.4–4.0% of all oxygen consumed inmitochondria is transformed into the superoxide radical (O2

��)(Evans et al., 2002; Carreras et al., 2004; de Moura et al., 2010),which is transformed to hydrogen peroxide (H2O2) by the detoxifi-cation enzymes copper/zinc superoxide dismutase (Wallace, 2005;Pieczenik and Neustadt, 2007) or manganese superoxide dismu-tase (MnSOD) and then to water by glutathione peroxidase (GPX)(de Moura et al., 2010). Another important enzyme implicated inH2O2 detoxification is catalase (CAT) (Bai and Cederbaum, 2001;Salvi et al., 2007). When these enzymes cannot transform ROS fast

ture components of the ETC complexes. NADH and FADH2 proceed from differentup through the CU. Ca2+ mitochondria level is dependent on the level of Ca2+ within

r; cyt c, cytochrome c; ER, endoplasmatic reticulum; ETC, electron transport chain;e space; Mal-Asp, Malate/Asparatate; mtDNA, mitochondrial DNA; OMM, outere/dihydroxyacetone.)


enough, oxidative damage occurs and accumulates in mitochon-dria (Sies, 1993; James and Murphy, 2002; de Moura et al., 2010).

Additionally, nitric oxide (NO) is produced inside the mitochon-dria by mitochondrial nitric oxide synthase (Carreras et al., 2004)and also diffuses into the mitochondria from the cytosol. WhenNO reacts with O2

�, another radical (peroxynitrite, ONOO�) isproduced.

ROS and RNS cause severe damage to macromolecules whenoverproduced and consequently have been linked to aging, degen-erative pathologies, and death (Balaban et al., 2005). However,when generated in a controlled amount, ROS may also play impor-tant signaling roles in various redox-dependent processes, includ-ing apoptosis (Bayir et al., 2006; Kagan et al., 2009) and cellproliferation (Fruehauf and Meyskens, 2007; Frantz and Wipf,2010).

1.2. Mitochondrial biogenesis

In conditions of cellular stress or in response to environmentalstimuli that require increases in ATP consumption, such as calorierestriction and exercise, the mitochondrial biogenesis is activated,resulting in a higher mitochondrial mass and mitochondrial DNA(mtDNA) (Piantadosi and Suliman, 2012; Brenmoehl and Hoeflich,2013). On the contrary, inhibition of mitochondrial biogenesis byoxidative damage or mtDNA-mutations disrupt metabolism, en-ergy production and oxidative stress resistance and it has beenassociated with the development of age-related degenerative dis-eases, especially in tissues like brain or muscles that particularlyrely on high energy (Brenmoehl and Hoeflich, 2013).

Mitochondrial biogenesis is very complex and requires the con-certed and synchronized action of numerous processes that includesynthesis of mtDNA encoded proteins, synthesis and import (trans-lation) of nuclear encoded proteins and assembly of the dual genet-ic origin derived proteins and mtDNA replication (Scarpulla, 2011).

Mitochondrial biogenesis is regulated mainly at the level oftranscription and numerous nuclear-encoded mitochondrial genesmust be expressed in synchrony with the 13 mitochondrial-en-coded genes (Piantadosi and Suliman, 2012). A large number ofproteins such as cyt c, NADH dehydrogenase, citrate synthase,uncoupling proteins (UCP) 2 and 3, superoxide dismutase (SOD),ATP synthetase and mitochondrial transcription factor A (TFAM)are transcribed in the nucleus and imported into mitochondria(Scarpulla, 2011; Menzies and Hood, 2012). The TFAM, the mito-chondrial transcription factor B2 (TFB2) and the RNA polymerasec are the principal elements of mitochondrial gene expression. In-stead, mitochondrial translation implicates a second homologue ofTFB2, named TFB1, which also regulates the methylation state ofthe mitochondrial ribosome.

Several nuclear transcription factors including nuclear respira-tory factors 1 and 2 (NRF1 and NRF2), estrogen related receptora, the cAMP response element (CREB) and ying yang 1 transcrip-tion factor (YY1) regulate the expression of nuclear encoded mito-chondrial proteins (Scarpulla, 2011). Other genes which areimportant for mitochondrial biogenesis include the nuclear-en-coded proto oncogenec-Myc, an activator of the peroxisome prolif-erator-activated receptors coactivator 1a (PGC-1a) and themyocyte-specific enhancer factor 2A, which is a critical regulatorof oxidative capacity in skeletal and cardiac muscle activated byNRF1 and also activates growth factor and stress-induced genes,promoting cell growth and survival (Morrish et al., 2003; Danget al., 2005).

All the pathways regulating expression of nuclear encodedmitochondrial factors converge in PGC-1a, which is therefore con-sidered the master regulator of mitochondrial biogenesis (Wenz,2013).

The expression and activity of PGC-1a are induced by cellularstress and regulated by CREB and by PGC-1a itself via YY1 whichis a common goal of the mammalian target of rapamycin (mTOR)(Scarpulla et al., 2012; Wenz, 2013). Decline in mTOR activityinhibits YY1–PGC-1a function leading to decreased expression ofmitochondrial genes (Wenz, 2013). The activity and stability ofPGC-1a are strictly related to post-translation modifications, con-sequently the PGC-1a-modifying enzymes are indicators of cellularstress and therefore integrate PGC-1a-signaling into the cellularstress response.

AMP-activated protein kinase (AMPK), protein kinase B (PKB orAKT) and p38 mitogen-activated protein kinase (p38 MAPK) phos-phorylate and thus activate PGC-1a; activity of PGC-1a is also reg-ulated through sirtuin 1 (SIRT1) (Cantó and Auwerx, 2009), aNAD+-dependent deacetylase present in the nucleus.

The activity of SIRT1 depends on the NAD+/NADH ratio which inturn is increased by phosphorilated AMPK. Phosphorylation of Thr172 is needed for AMPK activation, and it has been demonstratedthat the serine/threonine kinase LKB1 directly mediates this event.Moreover, SIRT1 is able to stimulate AMPK through the deacetyla-tion/activation of LKB1, suggesting bidirectional interaction ofSIRT1 and AMPK.

AMPK signaling pathway appears to restrict cancer cell growthand proliferation activating some proteins that induce apoptosissuch as mTOR, tuberous sclerosis, p70S6 kinase, and eukaryoticelongation factor2. In addition, AMPK is activated by pharmacolog-ical compounds that modulate cell growth through regulation ofp53 as well as of p21, suggesting that it may also regulate the cellcycle checkpoint for preventing mutations (Mihaylova and Shaw,2011). Furthermore, AMPK activates the acute destruction of defec-tive mitochondria via the serine/threonine-protein kinase ULK1-dependent stimulation of mitophagy, and induces mitochondrialbiogenesis through PGC-1a-dependent transcription (Mihaylovaand Shaw, 2011).

1.3. Mitochondrial dysfunction

In bioenergetics and cell biology the terms mitochondrial func-tion and dysfunction are widely employed, but strict definition isstill difficult. In general, abnormality in any of the processes inwhich mitochondria is involved can be named mitochondrial dys-function (Brand and Nicholls, 2011). The first mitochondrial dys-function was described in 1962, and since then the medicine hasadvanced in understanding the role that mitochondria play inhealth, disease, and aging (Pieczenik and Neustadt, 2007). Mito-chondrial disorders have been implicated in a wide number of hu-man diseases (Table 1), however, since symptoms vary from caseto case, a mitochondrial dysfunction can be difficult to diagnoseat its onset (Pieczenik and Neustadt, 2007).

Mitochondria damage is mainly associated with an increase inthe generation of mitochondrial ROS (mtROS): complexes I andIII are considered the principal sites of O2

�� production during OX-PHOS (Harper et al., 2004; Brandon et al., 2006; de Moura et al.,2010). Moreover, under certain conditions, non-mitochondrialgenerated ROS can enhance mtROS production: it has been demon-strated that many other ROS-producing enzymes, such as NADPHoxidase (Doughan et al., 2008) and xanthine oxidase (Baudryet al., 2008), can stimulate mtROS production, in a process knownas ROS-induced ROS (Li et al., 2013) (Fig. 2).

Lipids, proteins, OXPHOS enzymes and mtDNA are particularlyvulnerable to free radicals/ROS/RNS within the mitochondria. Di-rect damage to mitochondrial proteins declines their affinity forsubstrates or coenzymes and, therefore, decreases their functionalefficiency (Liu et al., 2002). In addition, damaged mtDNA causes adecrease in transcription and in the synthesis of the polypeptidesassociated with ETC (Ballinger et al., 1999, 2000). Once a

Table 1Acquired and inherited conditions in which mitochondrial dysfunction has been implicated (modified from Pieczenik and Neustadt (2007)).

Acquired conditions Inherited conditions

Diabetes and cardiovascular diseases Kearns–Sayre syndromeHuntington’s disease Leber hereditary optic neuropathyCancer, including hepatitis C virus-associated hepatocarcinogenesis Mitochondrial encephalomyopathy, lactic acidosis and stroke-like syndromeAlzheimer’s and Parkinson’s disease Myoclonic epilepsy and ragged-red fibersBipolar disorder, schizophrenia and anxiety disorders Leigh syndrome subacute sclerosing encephalopathyFatigue, including chronic fatigue syndrome, fibromyalgia and myofascial pain Neuropathy, ataxia, retinitis pigmentosa, and ptosisAging and senescence Myoneurogenic gastrointestinal encephalopathy

Fig. 2. Schematic model of mitochondrial oxidative damage. During mitochondrial respiration a small amount of the molecular oxygen consumed by cells is converted intoO2�� by reactions occuring in complex I and III. MnSOD enzyme converts O2

�� to H2O2 which can be converted into H2O by GPX or PRX. H2O2 can also react with Fe2+ to produce�OH. This radical could attack mtDNA, decreasing mRNA and altering the expression of proteins essential for ETC. See text for details. (Abbreviations: �OH, hydroxyl radical;ATP, adenosine triphosphate; cyt c, cytochrome c; GPX, glutathione peroxidise; H2O2, hydrogen peroxide; IMM, inner mitochondrial membrane; IMS, intermembrane space;MnSOD, manganese superoxide dismutase; mRNA, messenger RNA; mtDNA, mitochondrial DNA; O2

��, superoxide radical; OMM, outer mitochondrial membrane; PRX,peroxidation enzymes.)


mitochondrion is damaged, its functionality can be further com-promised by increasing the cellular requirements for energy repairprocesses (Aw and Jones, 1989).

Complex I is particularly susceptible to NO-induced damageand its dysfunction has been associated with Parkinson’s disease(Perier et al., 2005), Leber hereditary optic neuropathy, and otherneurodegenerative conditions (Schon and Manfredi, 2003); com-plex III activity can be reduced by the inflammatory mediator tu-mor necrosis factor a (TNF-a), increasing ROS production anddamaging mtDNA (Suematsu et al., 2003) resulting in mitochon-drial impairment (Moe et al., 2004).

Also metabolic dysregulation may cause mitochondrial dys-function. Micronutrients and other metabolites are essential cofac-tors for the synthesis and function of mitochondrial enzymes andother compounds that support mitochondrial function (Table 2),thus diets deficient in vitamins and minerals can accelerate mito-chondrial damage (Pieczenik and Neustadt, 2007).

The expression, concentration or maximum activity of ETC com-plexes or metabolic enzymes, such as complex I, complex IV or tri-carboxylic acid cycle (TCA) enzymes, are a very common approachto address mitochondrial bioenergetic dysfunction (Brand andNicholls, 2011). In isolated mitochondria the simplest and mostrevealing test for energetic dysfunction is the measurement ofmitochondrial respiratory control through the assessment of mito-chondrial respiratory control ratio (RCR), defined as the rate of res-piration in state 3ADP (where ATPase functions and electron

transport accelerates) and in state 4 (where [ATP]/[ADP] ratioreaches the steady state, proton re-entry through the synthasestops and respiration slows down). State 3ADP is controlled by theactivity of ATP turnover (adenine nucleotide translocase (ANT),phosphate transporter and ATP-ase) and substrate oxidation(including substrate uptake, ETC complexes, processing enzymes,pool sizes of cyt c and ubiquinone and O2), while state 4 is con-trolled mainly by the proton leak and any ATPases that recycle syn-thesized ATP as ADP. Therefore, RCR is strongly influenced byalmost every functional aspect of OXPHOS and this complexity isits main strength: a change in almost any aspect of OXPHOS leadsto a change in RCR, making it a good indicator of dysfunction(Brand and Nicholls, 2011). In fact, a high RCR means that mito-chondria have a high capacity for substrate oxidation and ATPturnover and a low proton leak and therefore a good functionalitywhile a low RCR usually indicates dysfunction (Brand and Nicholls,2011).

In general, mitochondrial dysfunction and ROS are intimatelylinked in a cellular death spiral that underlies a large number ofhuman pathologies (Van Houten et al., 2006; Pieczenik and Neus-tadt, 2007).

1.3.1. ApoptosisGrowing evidence has shown that cell death can be induced by

three different mechanisms: autophagy (programmed cell deathII), oncosis (programmed cell death III or necrosis) and apoptosis

Table 2Key nutrients required for proper mitochondrial function (modified from Pieczenik and Neustadt (2007)).

Iron, sulfur, vitamins B1, B2, B3, cysteine, magnesium, manganese, lipoic acid Required for cell catabolic pathways that lead to NADH/FADH2 productionCoASH, carnitine, etc. necessary for b-oxidation

Citrulline, ornithine, etc. necessary for urea cycleSynthesis of heme for heme-dependent enzymes in the TCA cycle require several nutrients including iron,

copper, zinc and vitamin B6

Synthesis of L-carnitine requires vitamin CVitamins B2, B3, B5 and lipoic acid Required for pyruvate dehydrogenase (PDH) complexUbiquinone (CoQ10), vitamin B2, iron, sulfur and copper Required for ETC complexesUbiquinone (CoQ10), iron and copper Required for shuttling electrons between ETC complexes


(programmed cell death I). Autophagy is a caspase-independentprocess in which organelles degrade at an early stage of cell death,while the cytoskeleton remains conserved until the final phase ofthe dying process. On the other hand, oncosis is characterized bycellular swelling and cell membrane bursting that releases the cel-lular contents into the environment causing inflammatory cell sui-cide (Kerr, 1971; Lockshin and Zakeri, 2004).

In contrast with autophagy and oncosis, apoptosis can be de-fined as a mechanism characterized by a series of different bio-chemical and morphological changes, including increase in ROSlevel, activation of caspases, cell shrinkage, chromatin condensa-tion and nucleosomal degradation (Wyllie, 1995; Vander Heidenet al., 1997; Simon et al., 2000). Excessive production of ROS maycontribute to the development of apoptotic cell death throughthe release of several apoptogenic factors such as cyt c, apopto-sis-inducing factor (AIF), and caspases (Qian et al., 2012).

Caspases are a family of cysteine proteases considered as thecentral regulators of apoptosis (Lin et al., 2012a). They contain acysteine residue in the active site and cut the substrate in differentsites next to an aspartate residue, according to their specificity(Chang and Yang, 2000; Kalimuthu and Se-Kwon, 2013). Caspasesare essential to transduce the apoptotic signal cascade and to con-nect cellular targets leading to programmed cell death (Wolf andGreen, 1999; Bantseev and Youn, 2006). Caspases are widely ex-pressed as inactive proenzymes in many cells and, once activated,are able to activate other procaspases, allowing the initiation of theprotease cascade. With this process it is possible to amplify theapoptotic signaling pathway leading to rapid cell death. Caspasesare identified and categorized into: initiators (caspase-2,-8,-9,-10),effectors (caspase-3,-6,-7) and inflammatory caspases (caspase-1,-4,-5) (Kalimuthu and Se-Kwon, 2013).

There are two different mechanisms that execute apoptosisaccording to various different stimuli: the death receptor-depen-dent pathway (extrinsic pathway) and the mitochondria-depen-dent pathway (intrinsic pathway) (Yao et al., 2008). The extrinsicapoptosis signaling pathway is mediated by the activation of cellsurface receptors (death receptors), able to bind specific ligandsto form a death inducing signaling complex (DISC) that transmitsthe apoptotic signals (Essack et al., 2011). Intrinsic apoptotic path-way, on the other hand, is characterized by membrane permeabil-ity that causes mitochondrial swelling, rupture of the OMM andrelease of proapoptotic factors from the IMS (e.g. cyt c) (Kalimuthuand Se-Kwon, 2013).

Apoptosis plays a crucial role in eliminating hyper-proliferatingcells from the system (Halder et al., 2008), therefore, induction ofapoptosis represents an efficient strategy for cancer chemotherapyand constitutes a reliable marker for evaluating and designing newchemotherapeutic agents to improve patient treatment outcome(Taraphdar et al., 2001).

1.3.1.1. The death receptor or extrinsic apoptosis pathway. Theextrinsic apoptosis pathway comprises several protein members,such as death receptors, tumor necrosis factor receptors (TNF-R),

Fas complexes, the membrane-bound Fas ligand (FasL), the Fas-associated death domain (FADD) and caspases 8 and 10, which ulti-mately activate the rest of the downstream, leading to apoptosis(Kalimuthu and Se-Kwon, 2013).

The Fas system is mainly recognized for its death-related func-tions, even if its involvement in several proliferative and inflamma-tory signaling pathways is not well defined (Krammer, 2000). Forexample, it is known that FasL is able to bind its receptor to formFas DISC, which contains the adaptor protein FADD and caspases8 and 10. The formation of DISC determines the activation of thesecaspases, which then directly trigger the executioner caspase-3. Insome cells, the activation of caspase 8 could be the only conditionto cause death; in other cells, on the contrary, caspase 8 interactswith the intrinsic apoptotic pathway by cleaving Bid (a pro-apop-totic member of the Bcl-2 family), to form the truncated Bid (tBid)which translocates to the mitochondria and results in the release ofcyt c (Krammer, 2000) (Fig. 3).

Alterations in the extrinsic pathway can lead to malignanttransformation: for example mutations or deletions of the Fas genehave been found in different hematologic malignancies (Landowskiet al., 1997). The extrinsic pathway of apoptosis can be abrogatedthrough several mechanisms, like the upregulation of inhibitorsof apoptosis proteins (IAP), such as cellular inhibitor of apoptosisprotein (cIAP) or X-linked inhibitor of apoptosis protein (XIAP).Other inhibitors of this pathway are fibroblast activation protein-1, FADD protein (interleukin, (IL)-1), convert enzyme-like inhibi-tory proteins and the soluble decoy receptors (DcR3, TRAIL R-3/DcR1 and TRAIL R-4/DcR2), that can be antagonized by the stimu-lation of FasL (Kalimuthu and Se-Kwon, 2013).

1.3.1.2. The mitochondrial or intrinsic apoptosis pathway. The intrin-sic mitochondrial pathway of apoptosis can be initiated by a vari-ety of upstream receptor-independent stimuli (such as radiation,drugs, toxins, hypoxia, hyperthermia, viral infections and free rad-icals), that converge to mitochondria favoring its dysfunction (Es-sack et al., 2011; Kalimuthu and Se-Kwon, 2013; Cavaliere et al.,2013). All of these stimuli cause changes in the IMM that resultin an opening of the mitochondrial permeability transition pore(MPTP) and determine the release of two main groups of normallysequestered pro-apoptotic proteins from the IMS into cytosol (Sae-lens et al., 2004). The first group of proteins consists of cyt c, sec-ond mitochondria-derived activator of caspases (Smac)/directIAP–binding protein with low PI (DIABLO) and the serine proteaseHtrA2/Omi (Kalimuthu and Se-Kwon, 2013). Cyt c promotes theformation of a multi-protein complex called apoptosome (Chinnai-yan, 1999; Hill et al., 2002) by the aggregation of caspase-9 to-gether with apoptotic protease activating factor 1 (Apaf-1) in thecytosol resulting in caspase-9 activation. For the activation ofapoptosome complex, ATP is also required. Caspase-9 then triggerscaspase-3, which in turn activates the rest of the caspase cascadeleading to apoptosis. The Smac/DIABLO release from the IMS intothe cytosol promotes apoptosis by binding to the IAP, able to con-nect directly to caspases, and inhibits their enzymatic activity (Du

Fig. 3. Extrinsic cell death pathway, mediated by TNF-R superfamily. Receptor-mediated cell death starts with the recruitment of adapter proteins, like FADD, able to engagewith death-effector domain-containing caspase-8 or -10. The formation of DISC determines the activation of these caspases, which then directly activate the executionercaspase-3. Moreover, caspase 8 could interact with intrinsic apoptotic pathway by cleaving Bid, to form the tBid, resulting in the release of cyt c. See text for details.(Abbreviations: cyt c, cytochrome c; DISC, death inducing signaling complex; FADD, Fas-associated death domain; FasL, Fas ligand; tBid, truncated Bid; TNF-R, tumor necrosisfactor receptors.)


et al., 2000; Verhagen et al., 2000). At the same time, HtrA2/Omi isreported to promote apoptosis by inhibiting IAP activity (Suzukiet al., 2001; Verhagen et al., 2002) (Fig. 4).

The second group of pro-apoptotic proteins is released frommitochondria during apoptosis and includes AIF, endonuclease G(Endo G) and caspase-activated DNase (CAD). AIF, a mitochon-drion-localized flavoprotein, promotes chromatin condensationand DNA degradation during apoptosis. AIF translocates to the nu-cleus causing DNA fragmentation and condensation of peripheralnuclear chromatin (Susin et al., 1999). This initial form of nuclearcondensation is referred to as ‘‘stage I’’ condensation (Susin et al.,1999; Daugas et al., 2000). Endo G is another mitochondrialenzyme that translocates to the nucleus, where it is able to cleavenuclear chromatin to produce oligonucleosomal DNA fragments(Li et al., 2001). Both Endo G and AIF function in a caspase-inde-pendent manner. CAD is an endonuclease that translocates to thenucleus after being released from the mitochondria; like Endo G,it causes oligonucleosomal DNA fragmentation (Enari et al.,1998). This later and more important chromatin condensation isreferred to as ‘‘stage II’’ condensation (Susin et al., 1999; Daugaset al., 2000).

The intrinsic and extrinsic apoptotic pathways converge to cas-pase-3, which activates the ‘‘caspase-activated deoxyribonucle-ase’’, cleaving its inhibitor and leading to nuclear apoptosis. Thedownstream caspases induce the crumbling of: (i) cytoskeletal pro-teins, protein kinases, DNA repair proteins, (ii) inhibitory subunitsof endonuclease and (iii) the destruction of cellular functions(Kalimuthu and Se-Kwon, 2013).

Caspases also influence cell cycle regulation, cytoskeletal struc-ture and signaling pathways, leading to morphologic changes thatare typically manifestations of apoptosis, such as DNA condensa-tion and fragmentation and membrane blebbing (Mancini et al.,1998).

1.3.2. Mechanisms of apoptosis1.3.2.1. Membrane potential collapse. Although a temporary loss ofDWm may occur in physiological circumstances due to the ‘‘flut-tering’’ of one or several IMM pores (Zoratti and Szabo, 1995;Kroemer et al., 1998), a long-lasting or permanent DWm disruption

is often associated with cell death during the intrinsic apoptosispathway (Zamzami et al., 1995, 2005; Petit et al., 1996; Marchettiet al., 1996; Martinou et al., 2000; Kim et al., 2012). DWm is pro-moted by diverse stimuli such as Bax, Bak, and tBid proteins, acti-vation of caspases (that may degrade OXPHOS complexes) andcytosolic metabolites which promote the opening of a voltagedependent, high conductance channel called MPTP (Kroemeret al., 2007). Decrease of DWm promotes secretion of AIF and EndoG leading to caspase-independent cell death through mitochon-drial membrane permeabilization (MMP) (Petit et al., 1996, 1997;Zamzami et al., 1996; Susin et al., 1996; Qian et al., 1997; Bhatta-charyya et al., 2005; Kuo et al., 2009), considered in many cases the‘‘point of no return’’ in the cascade of events leading to apoptosis(Kroemer et al., 1995; Green and Kroemer, 2004). MMP is alsocharacterized by the release of cyt c (second mitochondria-derivedactivator of caspase/direct inhibitor of apoptosis), the arrest of OX-PHOS and the accumulation of ROS as well (Kroemer et al., 2007).

In several models of MMP, DWm dissipation occurs in a cas-pase-independent manner (Green and Kroemer, 2004; Kroemerand Martin, 2005) immediately after OMM permeabilization, whilein some cases DWm dissipation requires caspase activation andIMM is not affected until the degradation phase of apoptosis starts(Kroemer et al., 2007). OMM permeabilization allows the release ofsoluble proteins that are normally retained in the IMS and it canresult from: (i) destabilization of mitochondrial lipids by pro-apop-totic signals, supporting the formation of pores, (ii) translocationfrom the cytosol to the OMM or conformational changes of pro-apoptotic members of the Bcl-2 family (Bax and Bak) to bind tocomponents of the MPTP, (iii) dissipation of DWm caused by thelong-lasting opening of the MPTP, associated with the loss ofanti-apoptotic interactions with HK, inducing the swelling of themitochondrial matrix, and (iv) activation of pro-apoptotic proteinsof the Bcl-2 family which can be assembled into large multimers,enabling the release of IMS proteins (Kroemer et al., 2007; Leeet al., 2010a).

Therefore, two MMP mechanisms may coexist: a Bax mediatedOMM permeabilization which happens independently of any effecton the IMM and a MPTP mediated permeabilization which engagesIMM. Either mechanism eventually leads to the permeabilization

Fig. 4. Mitochondrial apoptosis pathway. Cyt c allows the assembly of the apoptosome (Apaf-1, caspase-9 and ATP) that activates caspase-3 leading to cell death. IAP bindsdirectly to caspases and inhibits their enzymatic activity. This inhibitory function is controlled by the Smac/DIABLO and HtrA2/Omi. See text for details. (Abbreviations: AIF,apoptosis-inducing factor; Apaf-1, apoptotic protease activating factor-1; ATP, adenosine triphosphate; cyt c, cytochrome c; DIABLO, direct IAP-binding protein with low pI;Endo G, endonuclease G; IAP, inhibitors of apoptosis proteins; Smac, second mitochondria-derived activator of caspases.)


of both mitochondrial membranes, release of proapoptotic proteinsfrom IMS (e.g. cyt c), and functional collapse of the mitochondriaand apoptosis, without regard to the initial trigger. However, thesetwo models do not exclude each other, but may coexist in specificpro-apoptotic settings (Kroemer et al., 2007).

1.3.2.2. Cytochrome c roles. Cyt c is strongly associated with mito-chondrial lipids, especially CL, and may be mobilized by: (i) the dis-ruption of electrostatic interactions with CL (that depend on pHand ion strength), (ii) the oxidation of CL mediated by ROS or (iii)the CL-oxygenase activity revealed by cyt c itself. The release ofcyt c enhances the generation of ROS by complexes I and III, favor-ing CL peroxidation and further cyt c release (Ott et al., 2002; Ka-gan et al., 2005; Garrido et al., 2006).

Low amounts of cyt c are able to bind to type I triphosphoinos-itol receptor and remove such Ca2+-dependent inhibition, promot-ing uncontrolled release of Ca2+ from the endoplasmatic reticulumstores, mitochondrial Ca2+ accumulation, and therefore, ROS in-crease and Ca2+-mediated opening of the MPTP, favoring MMP,and thus apoptosis (Boehning et al., 2003).

Once in the cytoplasm, cyt c promotes the assembly of the so-called apoptosome, a molecular platform for the activation ofpro-caspase-9 that includes Apaf-1, and ATP/dATP (Kroemeret al., 2007). Caspase-9 acquires in this way the ability to activatethe downstream caspase cascade, which ends in apoptotic celldeath (Zou et al., 1999).

Moreover low amounts of cyt c released following a limitedMMP are sufficient to activate part of the caspase-3 pool (Kroemeret al., 2007), which can enter the IMS through the partially perme-abilized mitochondrial OMM and degrade essential components ofcomplex I of ETC (Ricci et al., 2004). In turn, this provokes respira-tory chain impairment and interruption of the electron flow in theIMM: this is followed by an intense generation of ROS, which pro-mote MMP by interacting with the MPTP and/or support furthercyt c release by oxidizing CL (Garrido et al., 2006).

1.3.2.3. ROS-dependent mitochondrial pathway. Often the progres-sive loss of DWm is accompanied by an increased production ofROS, which quickly saturate the antioxidative defense systemsand induce the functional impairment of mitochondria, by delay-ing OXPHOS and via feed-forward mechanisms on the MPTP. Thus,ROS production in mitochondria has been characterized as an earlypro-apoptotic event that occurs before cells endure apoptosis (Kro-emer et al., 2007).

In cancer cells, ROS can initiate cell transformation by causingalterations during DNA replication (Gackowski et al., 2002), whilein transformed cells, ROS play a significant role in the initiationand execution of apoptosis (Tsang et al., 2003; Liu et al., 2003;Djavaheri-Mergny et al., 2003). Therefore, the up-regulation of asort of anti-apoptotic proteins that act as cellular antioxidants,such as certain members of the Bcl-2 family, allows cancer cellsto escape apoptosis (Hockenbery et al., 1993; Frommel and Zarling,1999; Kurosu et al., 2003). The balance of ROS and antioxidant lev-els thus critically determine apoptosis in cancer cells, and disablingthe antioxidative defense systems by accelerating ROS productioncould promote apoptosis (Wenzel et al., 2005).

1.3.2.4. Bcl-2 family pathway. The regulation and control of mito-chondrial apoptotic events takes place through the members ofthe Bcl-2 family proteins (Cory and Adams, 2002), that can be con-sidered the key regulators of apoptosis (Youle and Strasser, 2008).

The main site of action of Bcl-2-family proteins is the mitochon-drial membrane (Kroemer and Reed, 2000): they may be dividedinto antiapoptotic multidomain proteins (Bcl-2, Bcl-XL Bcl-W,Bfl-1 and myeloid leukemia cell differentiation protein (Mcl-1)),which contain four Bcl-2 homology (BH) domains (BH1234) andproapoptotic multidomain proteins (Bax, Bak), which contain threeBH domains (BH123) and proapoptotic BH3-only proteins (Bid,Bad, Bim) (Letai et al., 2002). Anti-apoptotic Bcl-2 members actas inhibitors of apoptosis by blocking the release of cyt c, whilstpro-apoptotic members act as promoters (Reed, 1997). BH1234


proteins mainly reside in OMM, where they protect mitochondriaagainst MMP, by binding to and neutralizing the pro-apoptoticBcl-2 proteins, which on the contrary are able to induce MMP (Kro-emer et al., 2007). As a result, pro-apoptotic proteins endure posttranslational modification (dephosphorylation and cleavage),resulting in their activation and translocation to the mitochondria,leading in this way to apoptosis (Scorrano and Korsmeyer, 2003).

Anti-apoptotic members of the Bcl-2 family could act as inhib-itors of their pro-apoptotic counterparts, without any independenteffects on other mitochondrial proteins (Kroemer et al., 2007). Forexample, the suppression of MMP can be realized through directinteraction with the pore-forming Bcl-2 members, or indirectlyby neutralizing BH3-only proteins (Letai et al., 2002). In this caseanti-apoptotic molecules such as Bcl-2 and Bcl-XL prevent mito-chondrial pore formation through binding with pro-apoptotic pro-tein of Bcl-2 family or directly interacting with Bax by inhibiting itstranslocation to the mitochondria (Nomura et al., 1999; Martinouand Green, 2001; Karpinich et al., 2002) (Fig. 5).

1.3.2.5. MAPK pathway. Among the signaling pathways that re-spond to stress, mitogen activated protein kinases (MAPKs) path-ways are crucial for cell maintenance and proliferation (Wadaand Penninger, 2004). MAPKs are part of a system composed ofthree sequentially activated kinases, and, like their substrates, theyare regulated by phosphorylation. They consist of three familymembers: c-Jun N-terminal kinases (JNKs), p38-MAPKs and extra-cellular signal-regulated kinases (ERKs). It has been demonstratedthat JNKs and p38-MAPKs (also known as stress-activated proteinkinases; SAPKs) are directly involved in apoptosis, while ERKs areactivated in response to growth stimuli and therefore importantfor cell survival (Wada and Penninger, 2004).

JNK stress pathways participate in many different intracellularsignaling pathways. They can activate transcription factors andnon-transcription factors such as anti-apoptotic proteins Bcl-2and Bcl-xL, and are directly activated by tyrosine and threonineresidues-phosphorylation (Wada and Penninger, 2004).

It has been proposed that JNKs are important in controlling pro-grammed cell death or apoptosis; several JNKs associate with mito-chondria inactivating anti-apoptotic and activating pro-apoptoticproteins of the Bcl-2 family such as Bax, Bcl-2, Bcl-XL, Bad orBim, triggering in this way the mitochondrial apoptotic pathway(release of cyt c release and caspase activation) and negativelyinfluencing MMP (Kroemer et al., 2007). Moreover, it has beenreported that active JNK can causes the release of apoptogenic fac-tors, such as cyt c and Smac/DIABLO (Wada and Penninger, 2004).JNKs cascade can be activated by apoptosis signal-regulatingkinase 1 (ASK1), which is activated in response to variousproinflammatory stimuli and it is able to induce apoptosis alonga mitochondrial-dependent pathway (Kroemer et al., 2007).

In most cases simultaneously with JNKs, p38-MAPKs pathway isactivated (Wada and Penninger, 2004), which promotes cell deaththrough apoptosis induction in several different cellular models(Wada and Penninger, 2004; Junttila et al., 2008). At the same time,it has also been shown that p38-MAPK cascades enhance cellgrowth, survival and differentiation (Wada and Penninger, 2004).The molecular mechanisms that determine whether p38 signalingpromotes or inhibits cell proliferation and survival have not beenclarified but could potentially be correlated to the transformationstate of the cell or be linked to the nature of p38-activating signal(Junttila et al., 2008).

A far as the ERKs pathway is concerned, it is activated mainly inresponse to mitogens and growth factors: this pathway has longbeen associated with cell growth, proliferation and survival (Junt-tila et al., 2008). ERKs activity can suppress Fas-mediated apoptosisby inhibiting the formation of the DISC and promotes cell survival

through transcriptional up-regulation of anti-apoptotic proteins,such as Bcl-2 and Bcl-xL (Junttila et al., 2008).

Cell survival is related to ERK pathway activity in several cellu-lar models, whereas activation of p38 and JNK results in apoptosisinduction: these data suggest that ERKs pathway can be considereda survival factor and an important anti-apoptotic signal, while JNKand p38-MAP kinases exert opposite effects on apoptosis (Wadaand Penninger, 2004; Junttila et al., 2008) (Fig. 6).

1.3.2.6. Survival signaling via PI3K/AKT. The phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) pathway is a mitochondrialpathway of apoptosis initiated by a variety of upstream stimuliand strongly regulated by various factors (Kalimuthu and Se-Kwon,2013). The PI3K/AKT signaling cascade belongs to the critical sur-vival programs that are typically overactivated in human cancers,representing a key signal transduction pathway that mediates cellgrowth and blocks apoptosis (Kalimuthu and Se-Kwon, 2013).

AKT can lead to cell survival in different ways (Kalimuthu andSe-Kwon, 2013), regulating the apoptotic signal transduction di-rectly or indirectly (Kalimuthu and Se-Kwon, 2013). In the firstcase it can directly interfere with cell death pathways by phos-phorylating key apoptosis-regulatory proteins, which, in turn,determine a shift in the ratio of pro- and anti-apoptotic proteins,resulting in the inhibition of cell death (Kalimuthu and Se-Kwon,2013). PI3K/AKT pathway represents a key regulatory mechanismto direct the activity of pro- and anti-apoptotic Bcl-2 family pro-teins (Kalimuthu and Se-Kwon, 2013). AKT could phosphorylateBad of the Bcl-2 family, which makes Bad dissociate from theBcl-2/Bcl-X complex and lose its pro-apoptotic function (Kalimu-thu and Se-Kwon, 2013). In the same way AKT phosphorylatesBim (Bcl-2 interacting mediator of cell death), blocking its activa-tion (Qi et al., 2006). However, AKT can also cause phosphorylationof some anti-apoptotic factors, such as XIAP and induced Mcl-1,increasing their anti-apoptotic properties by improving their sta-bility (Dan et al., 2004; Maurer et al., 2006). AKT can also phos-phorylate HtrA2/Omi, thereby inhibiting apoptosis (Parcellieret al., 2008). Moreover, the phosphorylation of caspase-9 with anAKT-dependent process, blocks the induction of apoptosis (Car-done et al., 1998).

In addition, AKT can interfere with cell death program, indi-rectly by the phosphorylation of transcription factors such as Fork-head box O3 (FOXO3) or nuclear factor kB (NF-kB) (Kalimuthu andSe-Kwon, 2013). FOXO3 upregulates gene expression of the pro-apoptotic protein of Bcl-2 protein family and its function can beinhibited by AKT-phosphorylation in the PI3K signaling pathway(Kalimuthu and Se-Kwon, 2013). AKT also mediates activation ofNF-kB, by posphorylation of inhibitors of NF-kB (IkB) kinase thattransactivates wide range of anti-apoptotic/pro-survival NF-kB tar-get genes (Ozes et al., 1999) (Fig. 7).

1.3.2.7. NF-kB signaling pathways. NF-kB directly regulates theexpression of genes involved in different processes that play a cru-cial role in the development and progression of cancer, such as pro-liferation, migration and apoptosis (Dolcet et al., 2005).

In most cell types, NF-kB remains transcriptionally inactive, be-cause it is mainly cytoplasmic due to its interaction with IkB (Dol-cet et al., 2005). Its activation may result from different signalingpathways regulated by a variety of cytokines, growth factors andtyrosine kinases (Dolcet et al., 2005). NF-kB activation can alsobe related to an increased expression of members of the epidermalgrowth factor receptor, insulin growth factor receptor and TNF-Rfamilies (Dolcet et al., 2005). Moreover, activation of other signal-ing pathways, such as MAPK and PI3K/AKT, is also implicated inNF-kB activation (Dolcet et al., 2005).

NF-kB activation can occur through different molecular mecha-nisms: it is possible to identify a classical NF-kB pathway usually

Fig. 5. Bcl-2 proteins family regulates and controls mitochondrial apoptotic events. Bax and Bak can induce MMP independently or in combination with ANT and/or VDAC.BH3-only proteins can exert their pro-apoptotic action facilitating apoptosis induction by neutralizing anti-apoptotic proteins of the Bcl-2 family or binding to BH123proteins directly inducing apoptosis in a Bax/Bak-dependent mode. Anti-apoptotic Bcl-2-like proteins work through the inhibition of pore formation by Bax and Bak as well asthe inhibition of pores formed by ANT and/or VDAC proteins. See text for details. (Abbreviations: ANT, adenine nucleotide translocase; Apaf-1, apoptotic protease activatingfactor-1; ATP, adenosine triphosphate; cyt c, cytochrome c; MMP, mitochondria membrane permeabilization; VDAC, voltage dependent anion channel.)

Fig. 6. MAPK signaling pathways. MAPK signaling pathways are organized in modular cascades in which the activation of upstream kinases by cell surface receptors leads tosequential activation of a MAPK module (MAPKKK-MAPKK-MAPK). See text for details. (Abbreviations: ASK, apoptosis signal-regulating kinase; ERK, extracelular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MLK, mixed-lineage protein kinase;p38 MAPK, p38 mitogen-activated protein kinase; Raf, proto-oncogene serine/threonine-protein kinase; SAPK, stress-activated protein kinases.)


triggered by viral infections and pro-inflammatory cytokines andan alternative pathway activated by members of the tumor necro-sis factor (TNF) family (Dolcet et al., 2005).

NF-kB is involved in the stress responsive intracellular signalingpathways and it is extremely sensitive to alterations of cellular oxi-dative status, cell transformation, and apoptosis (Bode and Dong,2000, 2002). NF-kB may activate the transcription of several genesimplicated in the suppression of cell death by both mitochondrialand death receptor pathways, up-regulating the expression of

proteins that interfere with these apoptotic pathways (Dolcetet al., 2005).

Proteins of the TNF-a signaling cascade, such as the TNF-R-asso-ciated factors 2 and 6, may also be targets of NF-kB signaling path-way, leading to activation of pro-survival signaling stimulated byTNF (Wang et al., 1998).

Moreover, NF-kB is able to induce the expression of the IAP fam-ily proteins and some anti-apoptotic proteins of Bcl-2 family. IAPs(c-IAP1, c-IAP2, and XIAP) suppress apoptosis by direct inhibition

Fig. 7. Scheme of PI3K/AKT mediated anti-apoptotic regulations. AKT is activated by PI3K through phosphorylation, inactivating apoptogenic factors, Bad and caspase 9. AKTphosphorylates and inhibits pro-apoptotic protein Bax and Bim, while it phosphorylates and increases the activity of anti-apoptotic proteins XIAP and Mcl-1. AKT inhibitsapoptosis also through phospohrylation of HtrA2/Omi. AKT activates NF-kB, thus resulting in transcription of pro-survival genes including Bcl-XL and XIAP. FOXO3 action isinhibited by AKT-phosphorylation process. See text for details. (Abbreviations: AKT, protein kinase B; cyt c, cytochrome c; FOXO3, Forkhead box O3; IkB, inhibitors of NF-kB;IRS, insulin receptor substrate; Mcl-1, myeloid leukemia cell differentiation protein; mTOR, mammalian target of rapamycin; NF-kB, nuclear factor kB; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol-3,4,5-triphosphate; XIAP, X-linked inhibitor of apoptosis protein.)


of effector caspases (caspases-3, -6, -7, and 9), while the anti-apop-totic members of the Bcl-2 family (as Bcl-XL) can exert their actionantagonizing the function of the pro-apoptotic proteins (Dolcetet al., 2005).

Furthermore, NF-kB may regulate the transcriptional activity ofp53: an up-regulation of anti-apoptotic genes determines a reduc-tion of p53 levels, leading to the inhibition of p53-induced apopto-sis (Dolcet et al., 2005).

2. Effects of dietary compounds on mitochondrial functionality

The balance of cell proliferation, survival and death normallyregulates and maintains homeostasis in multicellular organisms.For these reasons, there is a general interest in identifying naturalbioactive compounds that could improve mitochondrial function-ality and regulate apoptosis process both in healthy and pathologicconditions. In this context, dietary compounds, mainly those ofvegetable origin, have been shown not only to stimulate mitochon-drial biogenesis but also to target signaling intermediates in apop-tosis-inducing pathways. In cancer cells, dietary compounds couldprotect against disease progression by enhancing elimination ofinitiated precancerous cells, acting like pro-apoptotic agents; onthe contrary in healthy cells these compounds usually protect fromapoptosis, performing as anti-apoptotic elements, and increasemitochondrial mass.

2.1. Dietary fats

In the last twenty years it has been widely demonstrated thatdifferences in dietary fat content and fatty acid saturation caninfluence the structure of lipid bilayers (Baroni et al., 1999), includ-ing those comprising mitochondrial membranes (Huertas et al.,

1991, 1992; Quiles et al., 1999a,b). Other consequences related tofatty acid intake comprehend perturbations in function of trans-porters (Hoch, 1992) and post translational protein modifications(Hasselbaink et al., 2002), mitochondrial membrane fluidity(Tsalouhidou et al., 2006), Ca2+ dynamics (Pepe et al., 1999; Paterg-nani et al., 2011), and gene expression involved in apoptosis, car-bohydrate and lipid metabolism (Fukui et al., 2013; Jump, 2008).

The omega-3 polyunsaturated fatty acids (n-3 PUFAs) aresupplied from vegetable oils under the form of a-linolenic acid(a-LNA), or from fatty fishes and marine food, in particulareicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. DHA isa major component of membrane phospholipid bilayers where itcontributes to the maintenance of the structural and functionalintegrity of cells and organelles. Although mammalian cellspossess the enzymes needed to elongate and desaturate a-LNA,the intake of dietary DHA and EPA provides these fatty acids forthe functions of organs and tissues (Al-Gubory, 2012). The n-3and n-6 PUFAs are implicated in the regulation of genes involvedin lipogenesis and cholesterolgenesis (Jump, 2008; Jump andClarke, 1999; Siculella et al., 2004a,b; Duplus et al., 2000), and theirdietary consumption can influence mitochondrial lipogenesis andfatty acid b-oxidation capacity. The main site for the progress offatty acid b-oxidation in mitochondria is the carnitine palmitoyltransferase system (CPT) which transports cytosolic long chainfatty acids-CoA from cellular cytosol in the mitochondrial matrixfor their oxidation. The CPT system is composed of three differentproteins: carnitine palmitoyl transferase 1 (CPT1), carnitine palmi-toyl transferase 2 (CPT2) and carnitine/acylcarnitine translocase(CACT). The inhibition of CTP1 by malonyl CoA in rat heart andskeletal muscle is influenced by the fatty acid composition of thediet. Safflower oil (SO) and evening primrose oil diets contain highlevels of linoleic acid, causing increased rates of b-oxidation (andthus higher CPT1 activity) as there is a lesser risk of losing too


much linoleic acid through catabolism (Power and Newsholme,1997). In rat-liver mitochondria, the dietary fatty acid compositionalso affects the activity of CACT, which exchanges cytosolicacylcarnitine for carnitine in the mitochondrial matrix. Inolive oil (OO)-fed rats CACT activity decreases compared to fishoil-enriched diet, which significantly increases it. No alteration ofcarnitine/palmitoylcarnitine exchange is observed with theSO-supplemented diet (Priore et al., 2012). Another protein of theIMM, the tricarboxylate carrier (TCC), that transports mitochon-drial acetyl-CoA into the cytosol and supplies NAD+ and NADPHrespectively for cytosolic glycolysis and lipid biosynthesis (Kaplanand Mayor, 1993), is influenced by dietary fatty acids consumption.TCC activity in rats decreases in parallel with TCC messenger RNA(mRNA) abundance, only upon n-3 PUFAs feeding. The administra-tion of long chain saturated fatty acid rich diets, or OO, high inoleate (C18:1 n-9) fails to inhibit TCC activity.

Membrane fatty acid composition, furthermore, may regulateETC enzyme activities, particularly in the heart, a tissue highly reli-ant on energy production supplied by mitochondria. In fact,monoinsatured fatty acids (MUFAs)-rich diet protects heartmitochondria better from aging-derived alterations than n-6PUFA-enriched diets, which require high amounts of antioxidantsto resemble MUFA effects (Quiles et al., 2010). Also mtDNA dele-tions and oxidative stress, typical of the aging process, are lowerin rat brain mitochondria when animals are fed with a MUFA-en-riched diet (Ochoa et al., 2011). It has also been found that n-3 PU-FAs and MUFAs rich oil supplementation allows alveolar bone toadapt to aging, maintaining mitochondrial turnover through bio-genesis or autophagy and avoiding the age-related inhibition ofmitochondrial ETC (Bullon et al., 2013). In general, MUFA andPUFA-enriched diets deeply affect either the structure or functionof mitochondria membranes depending on time and/or possibleco-modulators (e.g. exercise, xenobiotic, frying procedures, etc.):the former being protective while the latter increases oxidativedamage producing impairment of ETC activities and cytochromecontents (Barzanti et al., 1994; Quiles et al., 2001; Battino et al.,2002).

PUFAs also play an important role in mitochondrial Ca2+

homeostasis and function (Rohrbach, 2009). There is evidence thatdietary supplementation with DHA alters mitochondrial phospho-lipid fatty acid composition and delays Ca2+-induced MPTP open-ing (O’Shea et al., 2009; Khairallah et al., 2010a,b; Stanley et al.,2012). Highly reactive and oxidative aldehydes are end productsof PUFA peroxidation that trigger Ca2+-induced MPTP openingand apoptosis (Kristal et al., 1996); they also exert cytotoxicitydue to their reactivity with protein residues, and have the potentialto impair the mitochondrial function, via the alteration of glutathi-one (GSH) metabolism and oxidative stress induction (Lee et al.,2006a). It is important to highlight that PUFAs induce Ca2+ mobili-zation and efflux from mitochondria (Zhang et al., 2006) and thatthe release of PUFAs from mitochondria occurs during Ca2+-in-duced MPTP opening and mitochondrial swelling (Blum et al.,2011). Furthermore, the lowered efficiency of work performance,which occurs in isolated hearts from rats fed with a diet rich inn-6 PUFA, rather than n-3 PUFA, could be raised by mitochondrialCa2+ transport inhibition. After Ca2+-dependent stress, the Ca2+-dependent activation of pyruvate dehydrogenase (PDH) and mito-chondrial Ca2+ cycling can be manipulated by varying the ratio n-3/n-6 PUFA in mitochondrial membranes of young and aged rathearts through n-3 or n-6 PUFA-rich diet. The results show thatthe activation of Ca2+-dependent PDH can be augmented whenthe n-3/n-6 PUFA ratio is low (n-6 PUFA-rich diet) or attenuatedwhen this ratio is relatively high (n-3 PUFA-rich diet) (Pepe et al.,1999).

PUFAs susceptibility to peroxidation in biomembranes by cellu-lar ROS raises the question of oxidizing properties exerted by these

fatty acids, especially if their content is substantially augmented indiet. Mitochondrial membrane lipid peroxidation affects fluidityand permeability changes in mitochondria and loss of transmem-brane potential (Al-Gubory, 2012). Hence, it is not surprising thatmitochondrial function and production of ROS may be affectedby dietary fat intake. Notably, mitochondrial phospholipids havehigher MUFA amounts than n-6 PUFA.

Dietary intake of n-3 and or n-6 PUFAs may therefore be detri-mental to cellular function as ROS-mediated peroxidation of thesefatty acids can increase toxic products, which are potentially muta-genic and atherogenic (Feng et al., 2006): for example the incorpo-ration of n-3 PUFAs into mitochondrial membranes facilitatesapoptosis of colonocyte by enhancing ROS generated via OXPHOS(Chapkin et al., 2002).

Another concern regards supplementation with DHA since itmodifies the apoptotic pathways by disrupting the cellular antiox-idant enzyme systems. DHA inhibits the growth of epithelial colo-rectal adenocarcinoma cells, at least in part, through cyt c releasewhich triggers the expression of pro-apoptotic caspases (Naraya-nan et al., 2001). In intact HL-60 cells, n-3 PUFAs (EPA and docosa-pentaenoic acid), more than n-6 arachidonic acid (AA), stimulateROS generation and activate various types of caspase-like prote-ases, such as caspase-3, -6, -8, and -9, but not caspase-1. In addi-tion, PUFAs trigger the reaction leading to the cleavage of Bid, adeath agonist member of the Bcl-2 family, and also release cyt cfrom mitochondria into the cytosol (Arita et al., 2001, 2003). Theeffects of PUFAs c-linolenic acid and EPA involve the mitochondrialpathway of apoptosis induction leading to cyt c release, caspaseactivation, loss of DWm and DNA fragmentation in Walker 256 tu-mor growth in vitro (Colquhoun and Schumacher, 2001). Sincemitochondria can act as central executioners of apoptosis, EPAand DHA incorporation into colonocyte mitochondrial membranesowing to their high degree of unsaturation enhance susceptibilityto damage produced by ROS generated via OXPHOS. This, in turn,would compromise mitochondrial function, thereby initiatingapoptosis (Chapkin et al., 2002). In addition, DHA suppressesunconjugated bilirubin-mediated inhibition of SOD, GPX and cata-lase activities and induction of apoptosis in astrocytes (Beceriret al., 2013). PUFAs also regulate gene expression by activating li-pid-sensitive transcription factors, such as peroxisome prolifera-tor-activated receptors (PPARs) (Clarke, 2000): interestingly,SOD2 is a target gene of PPAR-c and myocardial SOD2 is down-reg-ulated both in transcript and protein levels in cardiac tissue ofPPAR-c knockout mice in the absence of externally or pathologi-cally induced oxidative stress (Al-Gubory, 2012).

2.2. Vitamins

Vitamins are essential micronutrients for human health mainte-nance, especially found in fruits and vegetables. Recently, liposol-uble vitamins, such as vitamins A and E, have attracted attentiondue to their effects on mitochondrial functionality, while the liter-ature data for hydrosoluble vitamins are still scarce.

2.2.1. Vitamin AVitamin A is a group of organic molecules that includes retinol,

retinal, retinoic acid, and several pro-vitamin A compounds(carotenoids). It can be obtained either directly from the diet orby the intake and conversion of carotenoids. Diverse members ofthis family have been widely used in the treatment of visual andskin conditions, such as acne and psoriasis. They also exhibitanti-proliferative and pro-apoptotic activity related to mitochon-drial pathways (Bushue and Wan, 2010). Vitamin A inhibits growthand induces differentiation in a variety of neoplasms, particularlyepithelial cancers and leukemia (Peehl et al., 1993; de-Medeiroset al., 1998; Xun et al., 2012). In adult T-cell leukemia for example,


retinoic acid induces apoptosis via down regulation of Bcl-xL andcaspase-3 activation (Fujimura et al., 2003), while retinol causeslipoperoxidation, MMP, drop in mitochondrial activity and in cellu-lar ATP levels, cyt c release and caspase-3/and -7 activation in aconcentration-dependent pattern, in rat liver mitochondria (Klamtet al., 2005) and in Sertoli cells (Klamt et al., 2008).

2.2.2. Vitamin EVitamin E is a group of lipophilic chain breaking antioxidants

composed of naturally occurring a-, b-, c- and d-tocopherols anda-, b-, c and d tocotrienols that are synthesized exclusively by pho-tosynthetic organisms (Nowak et al., 2012). The most commonforms of vitamin E can be found in high concentrations in manyvegetable oils such as corn, soybean, wheat germ, sunflower andSO (Birringer et al., 2010). Its antioxidant properties and the capac-ity of preventing either PUFAs oxidation or other events driven byfree radicals are well known. Vitamin E deficiency negatively af-fects mitochondrial structure and ETC activities accelerating agingprocesses (Armeni et al., 2003). In the last years possible anti- andpro-apoptotic mechanisms of a-tocopherol through the mitochon-drial pathway have been also proposed (Nowak et al., 2012). In theporcine renal endothelial cell line LLC-PK1 exposed to cyclosporinA (CsA), a-tocopherol supplementation reverts mitochondrial dys-function (characterized by MMP, Bax migration to mitochondria,DWm collapse, cyt c-release, and ROS production) avoiding apop-tosis (de Arriba et al., 2009). It also ameliorates similar pro-apopto-tic effects induced by amitriptyline in human fibroblasts (Corderoet al., 2009) and by ethanol in pups neurons (Heaton et al.,2011). In addition, at high doses it improves survival, brain mito-chondrial function and neurological performance in aging malemice, increasing state 3-respiration and Mn-SOD and complex Iactivities (Navarro et al., 2005).

In a human retinal pigment epithelial cell line, a-tocopherolpretreatment shows significant protection against decrease in cellviability, inhibition of the expressions of pAKT and p38MAPK in-duced by acrolein exposure and reduction of acrolein-inducedROS production. It also improves GSH levels and the activities ofmitochondrial complexes I, II and V (Feng et al., 2010). Further-more, a-tocopherol exerts protective effects against UVB-inducedapoptosis of chicken embryonic fibroblasts through Ca2+ release

Fig. 8. Classification of pol

reduction and Bcl2/Bax ratio up-regulation (Jin et al., 2011) andit decreases hepatic UCP2 expression as well as oxidative stress,improving mitochondrial function in mice with steatotic livers be-fore and after ischemia/reperfusion (Evans et al., 2009).

Although a-tocopherol is the most studied form of vitamin E,new findings have shown interesting properties of other vitamersand their corresponding metabolites, mainly as pro-apoptoticagents (Birringer et al., 2010). a-Tocopheryl succinate (a-TOS) forexample is a derivative of vitamin E with high in vitro and in vivoefficacy on different tumor cells. In breast cancer cells it inhibitsOXPHOS at complex I and II, promoting cell death through mtROSgeneration (Dong et al., 2008).

Over-production of ROS in combination with mitochondrialpermeabilization through preferential formation of Bak channelsare also implicated in a-TOS induced apoptosis in neuroblastomas(Kruspig et al., 2012), Jurkat T lymphoma and MCF7 breast adeno-carcinoma cells lines (Prochazka et al., 2010). It also induces anearly dissipation of the DWm and promotes accumulation of ROSfollowed by cyt c release and caspases activation in a model ofacute promyelocytic leukemia (dos Santos et al., 2012).

2.3. Polyphenols

Polyphenols are the most abundant dietary antioxidants; theyare extensive constituents of fruits, vegetables, grains, roots, choc-olate, coffee, tea, and wine (Scalbert et al., 2005; D’Archivio et al.,2007). All polyphenols contain one or more aromatic rings withone or more hydroxyl group as substituents. Depending on thenumber of these phenol rings and on the structural elementsbound to them, polyphenols are classified into different groups.The principal groups are: flavonoids, phenolic acids, phenolic alco-hols, stilbenes and lignans (D’Archivio et al., 2007) (Fig. 8).

2.3.1. FlavonoidsFlavonoids are the largest group of polyphenols and are divided

into 6 subclasses: flavonols, isoflavones, anthocyanins, flavanols,flavones and flavanones. All of them share two benzene ringsjoined by a linear three-carbon chain and a common carbon skele-ton of diphenyl propanes.

yphenols compounds.


2.3.1.1. Flavonols. The most widespread flavonoids are flavonols,with quercetin (3, 30, 40, 5, 7-pentahydroxy flavone) as the majorrepresentative compound found in a variety of foods, includingtea, brassica vegetables, capers, grapes, onions, shallots, apples,tomatoes, berries and red wine (Punithavathi and Stanely MainzenPrince, 2010; Kelly, 2011).

Quercetin and its glucosylated forms represent 60–75% of flavo-noid intake in an average diet (Bouktaib et al., 2002). In its struc-ture, quercetin presents three important functional groups whichare responsible for its antioxidant properties when reacting withfree radicals: the 4-oxo group in conjugation with the 2,3-alkene,the 3- and 5-hydroxyl groups and the B ring with o-dihydroxylgroups (Bors et al., 1990) (Fig. 9).

The antioxidant properties of quercetin might be ascribed to itsability to scavenge free radicals and to chelate transition metalions, such as Fe2+ and Cu2+ (Punithavathi and Stanely MainzenPrince, 2010). Several studies have reported a wide range of phar-macological properties for quercetin, including benefits againstinflammation (Chirumbolo, 2010), atherosclerosis (Ishizawa et al.,2011), hypertension, (Perez-Vizcaino et al., 2009) and neurodegen-eration (Ossola et al., 2009; Kelsey et al., 2010) among others. Inneurotoxin-induced hemi parkinsonian rats, quercetin acts as anantidote to rotenone, an inhibitor of the ETC complex-I, up-regulat-ing the complex activity in damaged or normal dopaminergic neu-rons. Pre-treatment with quercetin attenuates rotenone-inducedOH_� generation in the mitochondrial fraction and increases endog-enous antioxidant enzyme (CAT and SOD) activities, completelyreverting the striatal dopamine cell loss (Karuppagounder et al.,2013). Quercetin supplementation also reverses inhibition of respi-ratory chain complexes (complexes II, IV and V) induced by 3-nitropropionic, restores ATP levels, attenuates mitochondrial lipidperoxidation and prevents mitochondrial swelling in an inducedmodel of Huntington’s disease (Sandhir and Mehrotra, 2013).Moreover, in isolated mitochondria from rat duodenum epitheliumor in Caco-2 cells, low concentrations of quercetin protect againstcomplex I inhibition by non-steroidal anti-inflammatory drugs

Fig. 9. Chemical structures o

(aspirin, indomethacin, diclofenac, piroxicam and ibuprofen) in aconcentration dependent manner. Its protective action resides inthe ability to behave as a coenzyme Q-mimetic molecule, allowinga normal electron flow along the whole ETC (Sandoval-Acuña et al.,2012). In hepatic mitochondria, pre-treatment with quercetin alle-viates lipid infiltration, membrane rupture and cristae destructioninduced by the chronic administration of alcohol, and mitigatesethanol-stimulated ROS generation. Furthermore, it reduces lipidperoxidation and reverses GSH depletion and Mn-SOD inactivation.In addition to oxidative stress relieving, quercetin prophylaxis nor-malizes DWm and MMP in ethanol-fed rats (Tang et al., 2012). Mit-igation of DWm loss is also implicated in the protective effects ofquercetin pre-treatment against anoxia/reoxygenation injury inrat primary cardiomyocytes (Tang et al., 2013). As a cardio-protec-tive agent, quercetin in combination with a-tocopherol also pre-serves the integrity of heart tissue and restores normalmitochondrial function in isoproterenol-induced myocardial-in-farcted rats. Quercetin and a-tocopherol protect the heart frommyocardial damage by scavenging free radicals and thereforeblocking lipid peroxidation in mitochondria. Administration ofboth compounds normalizes GSH-dependent enzymes activitiesand GSH levels in treated rats. It also decreases calcium levelsand enhances ATP levels preventing loss of ionic gradients andmaintaining the structure and function of mitochondrial mem-brane (Punithavathi and Stanely Mainzen Prince, 2010).

In addition to these beneficial effects quercetin also promotesapoptosis in different cancer cell lines preventing, therefore, tumorprogression. In non-small cell lung cancer, it strongly inhibits cellproliferation and increases apoptotic cell populations through thedown-regulation of NF-kB (Youn et al., 2013) which is also impli-cated in the antiproliferative effects of this compound on cervicalcarcinoma HeLa cells (Vidya Priyadarsini et al., 2010). In the samecellular line, quercetin increases the expression of the pro-apopto-tic Bax proteins, cytosolic cyt c, Apaf-1, p53, caspases-9 and -3, andpoly (ADP-ribose) polymerase (PARP) cleavage and reduces theexpression of the anti-apoptotic AKT, Bcl-2, Bcl-xL and Mcl-1. It

f principal polyphenols.


also induces DWm depolarization (Vidya Priyadarsini et al., 2010;Bishayee et al., 2013). Up-regulation in a dose dependent mannerof Bax protein expression, caspase-3 and 9 activation, cyt c releaseto the cytosol as well as a significant increment in mRNA levels ofthe cell cycle regulator p53 are also common events in quercetinmediated apoptosis in mouse neuroblastoma cells (Sugantha Priyaet al., 2014), rheumatoid arthritis fibroblast-like synoviocytes (Xiaoet al., 2013) and preneoplastic hepatocytes (Casella et al., 2014). Inaddition to its proapoptotic properties, quercetin is also able tomodulate the expression of critical cell cycle regulators (cyclinD1, and cyclin B1) and PPAR activation in preneoplastic hepato-cytes affecting cell proliferation and leading to a reduction of liverlesions (Casella et al., 2014). Finally, quercetin also induces apopto-sis and inhibits cell growth in human epidermoid carcinoma KBand KBv200 cells via the mitochondrial pathway but indepen-dently of the Bcl-2 or Bax protein regulation (Zhang et al., 2013).

2.3.1.2. Isoflavones. The main sources of isoflavones are soya and itsprocessed products, which contain the three main molecules: gen-istein, daidzein and glycitein. They are contained almost exclu-sively in leguminous plants. The basic structure of isoflavonecompounds is the flavone nucleus that is composed of 2 benzenerings linked through a heterocyclic pyrane ring (Fig. 9). Genisteinhas been originally considered a phytoestrogen, because of its sim-ilarity in structure and activity with estrogens, especially with 17b-estradiol (Banerjee et al., 2008).

Recently, genistein has attracted increasing interest due to itspharmacological safety and its involvement in a wide range of ben-eficial health effects related to prevention of breast (Lee et al.,1991; Fritz et al., 1998; Lamartiniere, 2000; Messina and Wood,2008;) and prostate cancers (Dixon and Ferreira, 2002), cardiovas-cular disease (Merz-Demlow et al., 2000; Wenzel et al., 2008),obesity (Orgaard and Jensen, 2008) and osteoporosis (Ma et al.,2008).

The effects of genistein on mitochondrial functions have beeninvestigated in different models: for example, in an obesity modelwith mice fed with high-fat diets a low-dose of genistein increasesmitochondrial enzyme activities (Lee et al., 2006b). In order todetermine whether aging could increase the vulnerability of thebrain to estrogen with drawal-induced mitochondrial dysfunction,COX activity and mitochondrial ATP content were measured inmiddle-aged ovariectomized rats treated with genistein. The ob-tained results show that genistein is able to reverse estrogen withdrawal-induced mitochondrial dysfunction, restoring COX activityand ATP levels, suggesting its possible implication to prevent age-related diseases (Shi and Xu, 2008). Direct involvement of geni-stein has also been demonstrated in MPTP opening (Salvi et al.,2002; Tissier et al., 2007), in ATP-ase function (Zheng and Ramirez,2000), in maintaining mitochondrial redox balance (regulating theratio of GSH/glutathione disulfide (GSSG)) and membrane integrity(Ding et al., 2011). Genistein affords protection against these dif-ferent dysfunctions through the amelioration of oxidative stress,the upregulation of different antioxidant signaling pathways andthe regulation of various apoptosis pathways (Siow and Mann,2010; Xu et al., 2009). For example, one of the common genisteinprotective mechanisms is the regulation of AKT survival signalingpathway, that leads to the induction of apoptosis in human pros-tate, breast and pancreatic cancer cells (Li and Sarkar, 2002; Stoicaet al., 2003; Banerjee et al., 2007) and in transgenic adenocarci-noma mouse prostate mice model (El Touny and Banerjee, 2007).In breast cancer cells, genistein exerts its anti-proliferative actionthrough the regulation of Bcl-2/Bax proteins expression and cas-pase-3 activation, leading to apoptosis of these cells (Katdareet al., 2002; Tophkhane et al., 2007), while in human vascularendothelial cells the concomitant involvement of the above

signaling pathways were found after genistein treatment againstoxidative stress (Xu et al., 2009).

Another important favorable mechanism elicited by genistein isthe regulation of MAPK pathways: the inhibition of TGF-a-medi-ated p38-MAPK activation and cell invasion by geinstein treatmenthas been highlighted in human prostate epithelial cells (Huanget al., 2005), while in embryonic rat primary cortical neurons fromischemic-injury, genistein stimulates the ERK-MAPK pathway ininhibiting cell death (Schreihofer and Redmond, 2009). A furthercerebral ischemia mouse model has demonstrated the antioxidantand neuroprotective effect provided by genistein: this isoflavonehampers mitochondria-dependent apoptosis pathway, attenuatingcaspase-3 activity and suppressing ROS-induced NF-kB activation(Qian et al., 2012). On the contrary, ROS generation can be consid-ered an important tool for the treatment of damaged cells: geni-stein increases ROS generation and consequently stimulatesAMPK activation in HT-29 human colon cancer cells (Hwanget al., 2005a), leukemia cells (Sánchez et al., 2008) and in 3T3-L1pre-adipocyte cells, inhibiting in this way the process of adipocytedifferentiation and apoptosis, suggesting its possible implication inthe treatment of obesity (Hwang et al., 2005b). Genistein also pre-vents low potassium-dependent apoptosis of rat cerebellar granulecells, preventing cyt c release and ANT opening (Atlante et al.,2010). Finally, it has been demonstrated that genistein promotesmitochondria biogenesis in injured renal proximal tubular cells,increasing SIRT1 expression and stimulating PGC-1a-activity/expression, leading to the activation of the mitochondrial biogene-sis program (Rasbach and Schnellmann, 2008).

2.3.1.3. Anthocyanins. Anthocyanins are water-soluble pigmentsabundant in fruits, especially those with red, blue and purple col-ors. They are also contained in red wine, certain cereals and certainvegetables such as onions, radishes and cabbage. Anthocyanins arefound as glycosides of their respective aglycones form, called anth-ocyanidins, exhibiting antioxidant and anti-inflammatory proper-ties as well as a variety of chemotherapeutic effects. Amongthese, the most common and studied dietary compounds are cyani-din (Cy), pelargonidin (Pg), delphinidin (Dp) and malvidin (Mv)glucosides. Their effects on mitochondrial functionality vary fromthe apoptosis modulation to the regulation of mitochondrial mem-brane potential, respiratory chain and mitochondrial permeability,as in the case of Pg, which reduces the ATP-dependent K+ channelsactivity in the IMM, acting as an electron acceptor (Grigoriev et al.,1999; Marinov et al., 2001). On human gastric adenocarcinomaAGS cells, Mv exhibits the most potent anti-proliferative effect,blocking the cell cycle at the G0/G1 phase. The occurrence of apop-tosis induced by Mv is confirmed by apoptotic bodies formation,caspase-3 activation and PARP proteolysis. After Mv treatment,apoptotic cells lose their DWm, Bax/Bcl-2 ratio and p38 kinaseexpression increase and ERK activity is inhibited (Shih et al.,2005). Dp induces a growth inhibition both in human cancer cellsand in normal human fibroblasts, blocking the first cells in S/G2phase and the latter at G0/G1 phase with a significant reductionin DWm (Lazzè et al., 2004). In hearth ischemia, delphinidin-3-glu-coside (Dp3G) and cyanidin-3-glucoside (Cy3G) were able to re-duce cytosolic cyt c directly and rapidly, differently frompelargonidin-3-glucoside (Pg3G) and malvidin-3-glucoside(Mv3G) that possess low cyt c reducing activities. Pre-perfusionof hearts with Cy3G prevents ischemia-induced caspase activation,while Dp3G and Cy3G support mitochondrial state 4 respirationeven in the presence of exogenous cyt c (Skemiene et al., 2013).The same result on the state 4 respiration is obtained with bilberryextract, rich in Mv3G, Mv-3-galactoside, and Cy-3-galactoside(Trumbeckaite et al., 2013). Cy3G, Dp3G and Pg3G are responsiblefor cytoprotection in endothelium cells from ONOO�-mediatedapoptosis, which leads to atherogenesis. The treatment with all


these anthocyanins prevented the loss of DWm, the activation ofcaspase-3 and -9, the inactivation of the PI3K/AKT pathway andthe increase in cytoplasmic Bax levels, counteracting also its trans-location into the nucleus (Paixão et al., 2011). Similarly Cy3G wasfound to protect human umbilical vein endothelial cells byONOO�-induced stress, reducing the suppression of mitochondrialrespiration, DNA damage and poly (ADP-ribose) synthetase activa-tion (Serraino et al., 2003). A pool of isolated anthocyanins frommeoru (Vitis coignetiae Pulliat) exerts antiproliferative, anti-inva-sive and apoptotic effects on human hepatoma Hep3B cells, signif-icantly inhibiting cell growth by reducing antiapoptotic proteinsexpression (Bcl-2, xIAP, cIAP-1 and cIAP-2) (Shin et al., 2009a).

However, the majority of the literature takes into account theevaluation of Cy effects alone, because this anthocyanin is widelydistributed in foods and novel antioxidant and possesses anti-pro-liferative activities. In HK-2 proximal tubular cells, Cy protects cellsfrom apoptosis through the inhibition of caspases and PARP cleav-age, the blocking of p53 and mitochondrial-mediated apoptosispathways, the suppression of ROS overproduction and the activa-tion of ERK and AKT pathways (Gao et al., 2013). Excessive gener-ation of ROS, together with MMP loss and cell death, is alsoprevented in rat primary cortical neurons subjected to oxygen–glu-cose deprivation (OGD) death induction (Bhuiyan et al., 2011,2012) and in pancreatic b cells of diabetic mice (Sun et al., 2012).The treatment of permanent middle cerebral artery occlusion inmice with Cy3G isolated from tart cherries blocks AIF release frommitochondria under oxidative stress and reduces brain superoxidelevels (Min et al., 2011).

Furthermore, treatment of human neuronal cell line (SH-SY5Y)with Cy 3-O-glucopyranoside and its metabolite Cy inhibitsH2O2-induced ROS formation, but only Cy inhibits H2O2-inducedapoptosis, avoiding mitochondrial functionality loss and DNAfragmentation (Tarozzi et al., 2007). In leukemic cell line HL-60,Cy-3-rutinoside extract induces apoptosis in a dose-dependentmanner, leading to the accumulation of peroxides and theROS-dependent activation of p38 MAPK and JNK. Notably, thisanthocyanin does not lead to ROS accumulation in normal periph-eral blood mononuclear cells (Feng et al., 2007). Finally, in porcineaortic endothelial cells, Cy3G treatment avoids the glycated lowdensity lipoprotein-related dysfunctions preventing upregulationof NADPH oxidase 4, O2

�_ production, and restoring the inhibitedactivity of Complex I and III. It also prevents cell mortality andimbalance between key regulators for cell viability, such as cleavedcaspase 3 and B cell Lyphoma-2 (Xie et al., 2012).

2.3.1.4. Flavanols. Differently from other classes of flavonoids, flav-anols are not glycosylated in foods. Their main representative com-pounds are catechin and epicatechin which are found particularlyin many fruits, vegetables and teas and have been regarded as ben-eficial due to their antioxidant properties (Scalbert and William-son, 2000).

2.3.1.4.1. Catechin. High levels of catechin are primarily foundin the skin and seed of many fruits such as apple and grapes, aswell as in red wine (Renaud and de Lorgeril, 1992). Chocolate isalso a significant source of this compound (Arts et al., 1999). Cate-chin possesses two benzene rings and a dihydropyran heterocyclewith a hydroxyl group on carbon 3 (Fig. 9). The A rings is similar toa resorcinol moiety while the B ring is similar to a catechol moiety.

In the last decade, catechin has attracted considerable attention,because of its powerful antioxidant properties and potential anti-cancer activities (Siddiqui et al., 2006). Catechin has preventive ef-fects of on tamoxifen-induced oxidative damage in mouse livermitochondria, through a marked attenuation of the oxidative stressparameters, such as lipid peroxidation, protein carbonyls and O2

��

production; it also restores the nonezymatic and enzymatic antiox-idants of mitochondria (as SOD and GPX), suggesting its potential

beneficial effects in the prevention of ROS-induced diseases (Tab-assum et al., 2007). As far as mitochondrial energetic processesare concerned, in isolated rat liver mitochondria, catechin unlikequercetin, does not significantly decrease ATP levels, but inducesMPT, suggesting a higher potential for apoptosis induction (Dortaet al., 2005). Catechin administration inhibits cataract-inducedapoptosis in lens epithelial cells, suppressing the increased Bax/Bcl-2 protein ratio and caspase-3 expressions induced by N-methyl-N-nitrosourea (Lee et al., 2010b). Similar effects have beenobtained against doxorubicin (DOX)-induced toxicity in rat heartcardiomyocytes cell line H9C2, where catechin treatment signifi-cantly inhibited DOX-induced intracellular ROS accumulation, de-creased the number of apoptotic cells, prevented DNAfragmentation, and inhibited apoptotic signaling pathways,increasing Bax/Bcl-2 ratio and preventing the activation of cas-pase-3 and -9 (Du and Lou, 2008). Similar effects are elicited bycatechin in human hepatocellular carcinoma (HepG2) cells, under-lying its hepatoprotective and anticancer functions (Jain et al.,2013). The prevention of caspase activation, in particular cas-pase-3 and -8, is a defensive mechanism of action implementedby catechin also in primary culture of rat cerebral cortical neurons(Ban et al., 2006) and in mouse nerve growth factor-differentiatedPC12 cells treated with oxidative agents (Lin et al., 2009).

2.3.1.4.2. Gallocatechin, epigallocatechin, and epigallocatechingallate. In tea, other abundant flavanols are gallocatechin, epigal-locatechin (EGC), and epigallocatechin gallate (EGCG). (�)-Epigal-locatechin-3-gallate is the ester of EGC (a flavan-3-ol with gallateresidue in an isomeric trans position) and gallic acid (a trihydroxy-benzoic acid), and its structure is characterized by two triphenolicgroups (Yao et al., 2008).

Interest in green tea polyphenols as cancer chemopreventiveagents has been increased all over the world due to their non-toxicnature and efficiency in a wide-range of organs (Lee et al., 2010a).This protective activity has generally been correlated to the power-ful scavenging and anti-oxidative capacity of high concentrationsof unpolymerised catechins and their gallates among which EGCGresults the most extensively investigated due to its relative abun-dance, wide range of biologic activities and powerful antioxidantproperty (Bhattacharyya et al., 2005; Yao et al., 2008).

In this sense different studies highlight the direct involvementof EGCG in mitochondria functionality and its related diseases. Inisoproterenol-induced cardio-toxicity rats, EGCG exerts its preven-tive effect on mitochondria damage by decreasing lipid peroxida-tion products and increasing antioxidant, TCA and ETC enzymes(Devika and Stanely Mainzen Prince, 2008a). Moreover, pre-treatment with EGCG maintains normal mitochondrial functioncounteracting the increase in Ca2+ levels and the decrease inNa+/K+-ATPase activity and ATP concentration caused by isoprote-renol (Devika and Stanely Mainzen Prince, 2008b).

Anti-aging effects of EGCG have also been found in human dip-loid fibroblasts (Meng et al., 2008) and in aged rat brain (Srividhyaet al., 2009) through the regulation of mitochondrial integrity, up-regulation of the antioxidant system and increment in the activi-ties of TCA enzymes and ETC complexes.

Preservation of mitochondrial complexes and citrate synthasefunctionality (Sutherland et al., 2005) as well as regulation of mito-chondrial K+-ATP channels (Song et al., 2010) are protective effectsof EGCG against hypoxia�ischemia and ischemia/reperfusion inju-ries, respectively. Similar results have been obtained in 3-nitro-propionic acid-induced neurotoxicity in rat brain mitochondria,where EGCG restores ETC activity as well as prevents the leakageof important mitochondrial matrix components into the extracel-lular space (Kumar and Kumar, 2009).

EGCG antioxidant effects have been also found in CYP2E1-dependent toxicity HepG2 cells (Jimenez-Lopez and Cederbaum,2004) and in cadmium-induced rat brain mitochondria damage


(Abib et al., 2011) where protection against depletion in membranepotential and lipid peroxidation, respectively, are the suggestedmechanisms.

Several studies have demonstrated that EGCG can exertanti-carcinogenic and anti-tumor effects both in vitro and in vivoin various cancer models through the involvement of the cellularapoptotic program. In fact, EGCG treatment shows positive effectin cell growth inhibition and apoptosis induction in human prostatecarcinoma cells by (i) increasing the expression of pro-apoptoticproteins (Bax, Bak) and reducing the anti-apoptotic protein levels(Bcl-2, Bcl-XL) (Kazi et al., 2002; Adhami et al., 2007; Siddiquiet al., 2008), (ii) inhibiting NF-kB pathway (Adhami et al., 2007)and (iii) decreasing IAP levels with consequently activation of cas-pase-3 and -6 (Kazi et al., 2002; Adhami et al., 2007; Siddiqui et al.,2008). Similar results have been obtained in human melanomacells (Nihal et al., 2005). In human pancreatic cancer cells EGCGpromotes cell death model increasing Bax, down-regulating XIAPlevels and stimulating JNK signaling cascade (Qanungo et al.,2005). Involvement of MAPKs pathway, in particular activation ofp38 and JNK signal, has also been demonstrated in human cervicalsquamos carcinoma HeLa cells (Chen et al., 2000), chondrosarcomacells (Yang et al., 2011) and colorectal carcinoma HT-29 cells (Chenet al., 2003), highlighting how these mechanisms may contributeto the chemiopreventive function of EGCG. Moreover, in humanastrocytoma U373MG cells, EGCG treatment attenuates the inflam-matory response induced by IL-1b + b-amyloid (25–35) fragment,not only suppressing the activation of p38 and JNK pathways butalso down-regulating NF-kB activation (Kim et al., 2007). On thecontrary, but with the same effect, in 30.7b Ras 12 cells derivedfrom JB6 mouse epidermal cell line transfected with a mutant H-ras gene, EGCG causes a rapid and sustained decrease in ERKs pro-tein levels inhibiting MAPK1/2-ERKs pathway (Chung et al., 2001).

Many different studies explain other mechanisms throughwhich EGCG can mediate apoptosis. In malignant B cells, includingmyeloma cells and Burkitt’s lymphoma cells, the protective effectof EGCG appears in association with the release of cyt c andSmac/DIABLO from mitochondria into the cytosol and the loss ofDWm (Nakazato et al., 2005). Furthermore, in human laryngealepidermoid carcinoma cells (Hep2) (Lee et al., 2010a) and in hu-man chronic myelogenous leukemia cells (Iwasaki et al., 2009),EGCG treatment mediates apoptotic cell death through a cas-pase-independent mechanism, allowing the release of AIF andEndo G from the mitochondria to cytosol, without influencingany aspects of the apoptotic pathway. The effect of EGCG on Ultra-violet B-induced PI3K activation in mouse epidermal JB6 Cl 41 cellshas also been investigated: the pretreatment of cells with EGCGinhibits PI3K/AKT activation, suggesting a beneficial effect of thistea polyphenol on such critical carcinogenesis pathway (Nomuraet al., 2001). It should also be taken into account that the involve-ment of EGCG in regulating apoptosis does not regard only theintrinsic pathway, but also the extrinsic cascade: in human mono-cytic leukemia U937 cells in fact, EGCG can bind to Fas system,activating the Fas-mediated apoptosis pathway and leading to can-cer cell death (Hayakawa et al., 2001).

The activation of AMPK can be considered an important regula-tory component of cancer therapy regulated by EGCG treatment: inmouse hepatoma cells, rat myoblast cells (Murase et al., 2009),mouse preadipocytes cells (Hwang et al., 2005b; Murase et al.,2009) and in human colon cancer cells (Hwang et al., 2007) EGCGtreatment activates AMPK and increases apoptosis resulting inanti-cancer effects. Similar results have been obtained in anin vivo study carried out in BALB/c mice (Murase et al., 2009). Final-ly, in fibroblast and lymphoblastoid cells obtained from Down’ssyndrome subjects, EGCG is able to restore OXPHOS capacity andto promote mitochondrial biogenesis through SIRT1/PGC-1a sig-naling pathways, increasing mitochondrial mass and overall

mitochondrial function by up-regulating NRF-1, TFAM andOXPHOS proteins levels (Valentia et al., 2013).

2.3.1.4.3. Theaflavins and thearubigins. Among the hundreds offlavanols, special attention must be given to theaflavins (TF) andthearubigins (TR) which are the two most important and abundantpolyphenols of black tea, a drink consumed world wide (Bhattach-arya et al., 2009). During the tea fermentation process, tea cate-chins (EGC and EGCG) are polymerized by polyphenol oxidase(released from crushed tea leaves) to form TF and TR (Fig. 9) (Hal-der et al., 2008).

Black tea polyphenols exhibit relevant biochemical and phar-macological properties that include antioxidant activities, induc-tion of apoptosis, inhibition of cell proliferation, cell cycle arrestand modulation of carcinogen metabolism (Kalra et al., 2005). Ina model system of E. coli, TF has dual effects in a dose-dependentway: at low doses it acts as an antioxidant, while at high doses itinhibits bacterial ATP-ase or Complex I. These results suggest thepossibility that TF can be used as a drug targeting Complex I orATP-ase of some pathogens or in some diseases (Li et al., 2012a).TF cardioprotective effects have been demonstrated against heartischemia/reperfusion injury, through the opening of K+-ATP chan-nels in the mitochondrial membrane, and through the inhibitionof MPTP opening (Ma et al., 2011).

TF has been widely investigated also for its anti-carcinogenic ef-fects. For example, in human prostate (Prasad et al., 2007) and inmammary epithelial carcinoma cells (Lahiry et al., 2008), TF causesapoptosis up-regulating Bax, caspase-3 and -9 and down-regulat-ing Bcl-2 levels. Similar results have been obtained in p53-mutatedhuman breast cancer cells, where the activation of executionercaspases and apoptosis is related to the stimulation of Fas deathreceptor pathway and the inhibition of PI3K/AKT cell survival sig-naling (Lahiry et al., 2010). Also in human medullar thyroid andcervical cancer cells the inversely modulation of PI3K/AKT pathwayis the main effect of TF apoptosis-treatment, in combinationrespectively with the up-regulation of p38/MAPK signaling cascade(Mazumdar et al., 2013) or the inactivation of NF-kB throughblocking IkB phosphorylation (Singh et al., 2013).

Although the content of TR is much higher than that of TF, inter-estingly, there are only few reports available on its potential anti-cancerous effects: in A375 human malignant melanoma cells aloneTR has been demonstrated to induce apoptosis, through the stim-ulation of JNK and p38 pathways or the increase of Bax/Bcl-2 ratio(Halder et al., 2008; Bhattacharya et al., 2009).

2.3.1.4.4. Proanthocyanidins. Proanthocyanidins (PA), or con-densed tannins, are high-molecular weight polimeric flavonoidsthat also belong to the class of flavanols, formed by monomericunits of flavan-3-ol (+ catechin and � epicatechin) (Fine, 2000).PA consumption decreases the risk of developing several illnesses,such as cancer, inflammation, oxidative stress and cardiovasculardiseases. The beneficial effects of PA are ascribed to their antioxi-dant properties, although they can also modulate gene expression.

Grape seed proanthocyanidins (GSPs) have been found to in-duce apoptosis in several cell lines. In A549 and H1299 non-smalllung cancer cells, GSPs increase the expression of pro-apoptoticprotein Bax, decrease the expression of anti-apoptotic proteinsBcl2 and Bcl-xl, cause a loss of MMP and activate caspases-9, -3and PARP. Furthermore, treatment with GSPs increases G1 arrestmediated by the activation of Cdki proteins (Cip1/p21 and Kip1/p27), and simultaneously decreases Cdk2, Cdk4, Cdk6 and cyclinslevels (Singh et al., 2011). The same pathways are involved in thecellular proliferation inhibition and cell death induction in humanepidermoid carcinoma A431 cells (Meeran and Katiyar, 2007). Inrat skeletal muscle, GSPs increase mitochondrial oxygen consump-tion through the stimulation of glycosidic metabolism and expres-sion of PPAR-c and PGC-1a. Furthermore, they decrease citratesynthase activity, OXPHOS (complexes I and II) and NRF1 expres-


sion, while they increase the activity of COX (Pajuelo et al., 2011a).In brown adipose tissue mitochondria, GSPs modulate the expres-sion of proteins involved in TCA and ETC (Pajuelo et al., 2011b), andthey also improve most of the parameters affected by cafeteriadiet-induced obesity, such as the decrease of Sirt1, NRF1, isocitratedehydrogenase 3c, COX5a and mitochondrial respiration (Pajueloet al., 2012). In cardiomyocytes, GSPs are able to counteract thetoxic effects of DOX treatment, including ROS production, celldeath, GSH/GSSG ratio decline and MMP disruption. Notably, GSPsdo not alter the proliferation-inhibitory effect of DOX in MCF-7 hu-man breast cancer cells (Li et al., 2010). PA are administered inassociation with DOX in several tumoral in vitro cell lines and inexperimental transplantation in vivo, reducing in some cases cellproliferation and MMP and increasing apoptosis rate to a greaterdegree than DOX treatment alone (Zhang et al., 2005a,b). GSPs pro-tect from myocardial injury even when it is induced by isoprotere-nol in rats, restoring the normal levels of mitochondrialcholesterol, mitochondrial enzymes, ETC enzymes and cyto-chromes b, c, c1 and aa3 (Karthikeyan et al., 2007, 2009). GSPs alsoexert cardioprotection in chick cardiomyocytes exposed to H2O2 orantimycin A through ROS scavenging and chelating iron (Shaoet al., 2003), and they are found to reduce the NF-kB and TGF-B1expression in rat diabetic cardiomyopathy (Cheng et al., 2007). Inmice hepatic and brain tissues, GSPs decrease ROS production,DNA fragmentation, lipid peroxidation and cyt c reduction due to12-O-tetradecanoylphorbol-13-acetate treatment (Bagchi et al.,1998).

Purificated oligomeric proanthocyanidines (POPAs) from cran-berry are found to affect the viability of neuroblastoma cell lines,causing a loss of DWm and an increase of ROS production, directlycorrelated to the modulation of apoptotic markers. In fact, POPAsreduce the expression of pro-survival (Bcl-2, Mcl-1, Bcl-xL) and in-crease pro-apoptotic Bcl family proteins (Bax, Bad, Bid), upregulateSAPK/JNK MAPK activity and downregulate PI3K/AKT/mTOR path-way components. In SMS-KCNR NB cells, POPAs delay the cell cycleprogression and induce cell death via TNF-R activity. Furthermore,POPAs upregulate cyclin D1 and downregulates CDK6 andp27 expression, blocking the cell cycle in G2/M phase which corre-lates with a decrease of the G0/G1 subpopulation (Singh et al.,2012).

Among PA, the more common and studied compounds areprocyanidins. Grape seed procyanidin extract (GSPE) causes cellgrowth arrest in oral squamous cell carcinoma OEC-M1p21(Cip1)/p27(Kip1) protein expression, while it is able to inhibitcell cycle in oral squamous cell carcinoma SCC-25 both arrestingG1 phase and inducing mitochondrial apoptosis through Bcl-2alteration (Lin et al., 2012b). Similarly, GSPE induces G1-phase ar-rest in pancreatic carcinoma cell line MIA PaCa-2, and triggersmitochondria-mediated apoptosis in pancreatic carcinoma cell lineBxPC-3 (Chung et al., 2012). Differently, in colorectal cell lines HT-29, SW-480 and LoVo, GSPE does not change the Bcl-2 levels, but itincreases apoptosis levels through the activation of caspase-3 andcleavage fragment of PARP (Hsu et al., 2009). In thymus cells H2O2-damaged, GSPE can inhibit apoptosis and decrease MMP (Li andZhong, 2004), while in DU145 prostate cancer cells, GSPE inducesapoptotic death, with a MMP loss and an increase in cyt c releasein cytosol, leading to an increase of cleaved fragments of PARPand caspases-3, -7 and -9 (Agarwal et al., 2002). In rat liver mito-chondria GSPE also suppresses lipid peroxidation induced by thecarcinogen phorbol-12-myristate-13-acetate (Lu et al., 2004).Grape seed procyanidin B2 is capable to counteract the negative ef-fects of lactadherin overexpression on endothelial cells in diabetesmellitus, such as increased apoptosis with up-regulation of Bax/Bcl-2 ratio, cyt c release, and caspase-9 and caspase-3 activation(Li et al., 2011). Oligomer procyanidins from grape seeds inhibitglioblastoma growth, the most common and lethal tumor type in

the brain, inducing G2/M arrest and decreasing MMP in U-87 cells,with just little toxicity on normal cells (Zhang et al., 2009a).

Other procyanidins derived from several natural sources havebeen tested for their mitochondrial effect. Apple procyanidins acti-vate the intrinsic apoptotic pathway in human colon cancer-de-rived metastatic cells, enhancing polyamine catabolism andmitochondrial membrane depolarization, but the depletion ofintracellular polyamines switches the apoptotic pathway fromintrinsic to extrinsic (Maldonado-Celisa et al., 2008). In trans-planted B16 mouse melanoma cells and BALB-MC.E12 mousemammary tumor cells, apple procyanidins, in particular pentamerand higher degree fractions, increase MMP and cyt c release, andactivate caspase-3 and caspase-9 (Miura et al., 2008). A pentamericprocyanidin cocoa-derived inhibits the proliferation of several hu-man breast cancer cells, with a specific dephosphorylation of sev-eral G1-modulatory proteins (Cdc2, forkhead transcription factorand p53) in MDA MB231 cells and, only for p53, in MDA MB-468cells (Ramljak et al., 2005). Finally, cinnamon-derived procyanidintype A trimer significantly attenuates the DWm depolarization inC6 glial cultures after exposure to OGD. Trimer 1 also attenuatesthe OGD-induced decrease in glutamate uptake, through a mecha-nism involving MPTP (Panickar et al., 2012).

2.3.1.5. Flavones and flavonones. The less common flavonoids areflavones, found only in celery and parsley and flavanones, foundin citrus fruits, tomatoes, some berries and mint (D’Archivioet al., 2007), for which no consistent effects have yet been reported.

2.3.2. Phenolic acidsPhenolic acids are divided in two groups: one derived from cin-

namic acid and the other from benzoic acid. Hydroxycinnamicacids consist mainly of coumaric, caffeic and ferulic acid, whichare rarely found in the free form, while the most commonly acidsderived from benzoic acid are gallic and ellagic acid.

2.3.2.1. Hydroxycinnamic acids. Caffeic acid (3,4-dihydroxycinnam-ic acid or CA) is one of the most common phenolic acids found pri-marily, in coffee (Chang et al., 2010) but also in white grape, wine,olive, spinach, cabbage and asparagus (Rice-Evans et al., 1996). Itderives from the 4-hydroxycinnamic acid and its basic structureis the catechol ring (Fig. 9).

CA exhibits multiple biological functions, including antioxidantpotential (Chung et al., 2006; Masuda et al., 2008), anti-bacterial(Almeida et al., 2006) and anti-inflammatory activity, anti-allergicproperties (Park et al., 2008), inhibition of peroxidation on LDL(Jayaprakasam et al., 2006), reduction of blood glucose levels(Hsu et al., 2000) and anticancer activity (Chung et al., 2006).

Regarding its antioxidant potential, different studies highlightthe involvement of CA against oxidative damage. Protective effectof CA on mitochondrial dysfunction has been demonstrated in iso-proterenol-induced myocardial infarction in rat heart mitochon-dria, by decreasing free radicals accumulation, increasingmultienzyme activities, reducing GSH and ATP levels and main-taining lipids and calcium (Kumaran and Prince, 2010). CA is alsoable to significantly attenuate oxidative damage and impairmentin ETC activity, against quinolinic acid-induced ex-vivo oxidativedamage, buffering mitochondrial and histological alterations inrats, highlighting its possible therapeutic effect (Kalonia et al.,2009). Similar results were obtained against intrahippocampal kai-nic acid-induced cognitive dysfunction in rat (Kumar et al., 2011)and against fatigue syndrome-induced behavioral, biochemicaland mitochondrial alterations in mice (Kumar et al., 2010), whereCA treatment restores the levels of ETC complexes (I, II, IV) and im-proves oxidative defense decreasing lipid peroxidation, nitrite con-centration, increasing SOD activity and redox ratio, and restoringGSH and CAT levels.


However little is still known about the molecular pathwaythrough which CA exerts its beneficial effects: nowadays, the mod-ulation of various apoptosis process is considered a key mechanismof CA action. For example, on human cervical cancer cells CA in-duces apoptosis by inhibiting Bcl-2 activity, leading to release ofcyt c and subsequent activation of caspase-3, suggesting that thiscompound stimulates apoptosis through the mitochondrial path-way, and that it may be a promising chemopreventive or chemo-therapeutic agent (Chang et al., 2010). The effect of CA has beentested in multidrug-resistant MCF-7/Dox human breast carcinomacells, where CA acts as a potentially chemiosensitizing agent (Ahnet al., 1997). On the contrary, a study conducted on human lungcancer cells A549 and H1299 demonstrates the protective effectof CA on paclitaxel-induced cell death. This effect is mediatedthrough the up-regulation of pro-survival Bcl-2 proteins and theactivation of NF-kB signaling pathway, indicating that CA can pro-vide chemoresistance to cancer cells (Lin et al., 2012c). Overall, theactual effect of CA in chemoresistant cells remains unclear.

In literature much more attention has been directed to a well-known CA derivate: caffeic acid phenetyl ester (CAPE), the esterof CA with phenethyl alcohol. It is a biologically active polypheno-lic component of honeybee propolis and it is also known as popularfolk medicine (Grunberger et al., 1998). CAPE possesses, as CA, abroad spectrum of biological activities including antioxidant (Jai-swal et al., 1997), anti-inflammatory (Mirzoeva and Calder, 1996)and anticancer effects (Frenkel et al., 1993). Antioxidative protec-tion of CAPE has been examined against cadmium-induced kidneymitochondrial injury in rat: pre-treatment with CAPE ameliorateschanges caused by cadmium, reducing mitochondrial swellingand dissipation of membrane potential, ROS production, mitochon-drial NO and malondialdehyde levels, and increasing SOD activityand thiols. However, the mechanisms, by which these effects arerealized, are still unknown (Kobrooba et al., 2012). In any case,CAPE is also able to limit the functional alterations of mouse brainand liver mitochondria submitted to in vitro anoxia–reoxygenation,protecting coupled respiration with decreases in state 4 and in-creases in state 3, inhibiting mitochondrial membranes fluidity de-crease and reducing lipoperoxidation and protein carbonylationincrease (Feng et al., 2008).

Concerning anticancer effects, CAPE is a potent and specificinhibitor of NF-kB activation as well as an inducer of apoptosis(Natarajan et al., 1996; Watabe et al., 2004). Confirmations of theseeffects have been obtained through different studies, carried out onhuman breast cancer models (Wu et al., 2011; Watabe et al., 2004),cholangiocarcinoma cells (Onori et al., 2009), human myeloid leu-kemia cells (Cavaliere et al., 2009), human medulloblastoma cellline (Lee et al., 2008a) and in human prostate carcinoma cell (McEl-eny et al., 2004). The results obtained in vitro and in vivo modelsare also interesting: CAPE significantly attenuates bacterial pepti-doglycan polysaccharide-induced colitis in rat macrophages cellline and in rats, inhibiting NF-kB pathway and reducing pro-inflammatory cytokine production (Fitzpatrick et al., 2001). How-ever, CAPE can exert its protective function also through othermechanisms. The release of cyt c and AIF or Smac/DIABLO frommitochondria to cytosol are processes CAPE-mediated in 1-methyl-4-phenylpyridinium-induced neurotoxicity in brain mito-chondria obtained from adult C57BL/6 mice (Fontanilla et al.,2011) and in human leukemic cells (Cavaliere et al., 2013).Moreover, down-regulation of caspase level has been observed fol-lowing CAPE treatment: in rat brains after pentylenetetrazole-induced status epilepticus (Yis� et al., 2013), in rat model of necro-tizing enterocolitis (Tayman et al., 2011) and in low potassiumapoptosis-induced rat cerebellar granule cells (Amodio et al.,2003), CAPE blocks or prevents apoptotic cell death reducing thelevels of caspase-3 and/or-9. Similar results were found in rat mod-el of transient focal cerebral ischemia and reperfusion, where CAPE

treatment reduces caspase-3 levels and up-regulates anti-apopto-tic protein Bcl-XL (Khan et al., 2007). On the other hand, pro-apoptotic effect of CAPE has been demonstrated in damaged cells:for example, in human coronary smooth muscle cells after exoge-nous platelet-derived growth factor-BB stimulation (Ho et al.,2012), human myeloid leukemia U937 cells (Jin et al., 2008) andin human leukemic HL-60 cells (Chen et al., 2001) CAPE exhibitsa growth inhibitory effect and induces apoptosis activating cas-pase-3, down-regulating Bcl-2 and increasing Bax protein levels.

A potential use of CAPE in the treatment of malignant brain tu-mors has also been suggested. In human astrocytoma cells, in fact,CAPE sensitizes these cells to Fas-induced apoptosis in a redox-dependent manner, through loss of mitochondrial transmembranepotential and subsequent cell death (Choi et al., 2007). In carbontetrachloride (CCl4)-induced hepatotoxicity in mice, CAPE showspotent hepatoprotective effects, markedly decreasing CCl4 inducedFas/FasL protein expression levels, and in turn attenuating caspase-3 and -8 activities (Lee et al., 2008b). Finally also the involvementof p38 MAPK pathway can be considered an important mechanismthrough which CAPE induces apoptotic cell death and contributesto its antitumor effects, as demonstrated in rat brain tumor C6 gli-oma cells (Lee et al., 2003).

2.3.2.2. Hydrobenzoic acids. Ellagic acid (3,7,8-tetrahydroxy [1]-benzopyrano[5,4,3-cde] [1] benzopyran-5,10-dione or EA) (Fig. 9)is a polyphenol derived from hydrolysable ellagitannins found inberries and nuts. It is released by the metabolism of ellagitanninsby the microflora in the gut (Larrosa et al., 2006; Hwang et al.,2010).

In recent years, not only the anti-mutagenic and anti-inflamma-tory properties of this polyphenol have been reported but also itscharacteristics as a potent anti-carcinogenic agent (Hwang et al.,2010). It exhibits excellent antioxidant activity, radical scavengingcapacity and prevents Fe2+/Cu2+ induced formation of ROS (Çeribasiet al., 2012).

In human umbilical vein endothelial cells, EA mitigates oxidizedlow density lipoproteins (oxLDL)-induced apoptosis regulating theBcl-2/Bax ratio and activating the PI3K/AKT/eNOS signaling path-way. Pre-treatment with EA decreases ROS generation and intra-cellular Ca2+ in a dose-dependent manner and reverses NF-kBactivation triggered by oxLDL (Ou et al., 2010). It also preventsROS production, mitochondrial depolarization, necrotic cellulardamage, and therefore increases cell viability, in hepatocytes ex-posed to vitamin K3 and rotenone which induce oxidative stress(Hwang et al., 2010). In addition, it presents protective effectsagainst DOX-induced testicular and spermatozoal toxicity associ-ated with oxidative stress in male rats. A prior administration ofEA increases CAT and GPX activities and improves Bcl2/Bax ratio(Çeribasi et al., 2012). Moreover, EA pre-treatment regulates apop-totic genes expressions and enhances ETC enzymes activities inrats exposed to isoproterenol-induced myocardial infarction (Kan-nan and Quine, 2013).

On the other hand, EA can directly inhibit CaCo-2, MCF-7, Hs578T and DU 145 cells proliferation by means of ATP reduction act-ing as an anti-carcinogenic agent (Losso et al., 2004). In humanbladder cancer cell lines T24, it inhibits cell proliferation by p38-MAPK mediated caspase-3 activation (Li et al., 2005; Qiu et al.,2013).

In human neuroblastoma SH-SY5Y (Fjaeraa and Nånberg, 2009;Alfredsson et al., 2014), HL-60 acute myeloid leukemia (Hagiwaraet al., 2010), ovarian carcinoma ES-2 and PA-1 (Chung et al.,2013) and TSGH8301 human bladder cancer cells (Ho et al.,2013), suppression of cell proliferation and induction of apoptosisby EA are associated with alterations of DWm, activation of cas-pase-9 and -3, increase in proapoptotic protein Bax and decreasein the levels of antiapoptotic protein Bcl-2.


In addition to these mitochondrial pathways, EA can also induceapoptosis by caspases-6 and -8 activation and the cleavage of PARPin human prostate carcinoma PC3 cells (Malik et al., 2011) as wellas in the 7,12-dimethylbenz-[a]-anthracene-induced hamsterbuccal pouch carcinogenesis model, in which the expressionof Smac/DIABLO and cyt c release also increases (Anitha et al.,2013).

In human pancreatic cancer tissues EA stimulates apoptosisthrough inhibition of the pro survival transcription factor NF-kBand inhibits the activation of AKT (Zhao et al., 2013).

2.3.3. Phenolic alcoholsThe principal phenolic alcohols are tyrosol (4-hydroxypheny-

lethanol) and hydroxytyrosol (3,4-dihydroxyphenylethanol) (HT)which are mainly contained in extra virgin olive oil (Owen et al.,2000; Cabrini et al., 2001). Other sources of tyrosol are beer, redand white wine (Covas et al., 2003).

HT may stimulate the mitochondrial biogenesis that leads toenhancement of mitochondrial function and cellular defense sys-tems. In 3T3-L1 adipocytes, HT stimulates the promoter transcrip-tional activation and protein expression of PGC-1a (the centralfactor for mitochondrial biogenesis) and its downstream targets,including NRF1 and NRF2 and TFAM, which leads to an increasein mtDNA and in the number of mitochondria. The mechanisticstudy of the PGC-1a activation signaling pathway demonstratedthat HT is an activator of 50AMPK and up-regulates gene expressionof PPAR-a, CPT-1 and PPAR-c. HT enhances mitochondrial function,increasing activity and protein expression of mitochondrial com-plexes I, II, III and V, increasing oxygen consumption, anddecreasing free fatty acid contents in the adipocytes (Hao et al.,2010). Also in ARPE-19 human retinal pigment epithelial cells, acellular model of smoking- and age-related macular degeneration,HT exerts a protective function against oxidative damage inducedby acrolein, an environmental toxin and endogenous end productof lipid oxidation, through the activation again of PGC-1a andnuclear factor-E2-related factor 2 (Nrf2). Activation of Nrf2leads to stimulation of phase II detoxifying enzymes, including c-glutamyl-cysteinyl-ligase (GCL), NADPH-quinone-oxidoreductase1 (NQO-1), heme-oxygenase-1 (HO-1), SOD, peroxiredoxin and thi-oredoxin (Liu et al., 2007; Zhu et al., 2010). In the same cell line,tert-butyl hydroperoxide (t-BHP)-induced GSH reduction causesDWm loss and apoptosis. HT-induced GSH enhancement andinduction of Nrf2 target gene (GCLc, GCLm, HO-1, NQO-1), mRNAare inhibited by Nrf2 knockdown, suggesting that HT augmentsGSH through Nrf2 activation. In addition, HT activates mTOR/p70S6-kinase and PI3/AKT pathways, both of which contribute tosurvival signaling in stressed cells, as well as JNK, inducing p62/SQSTM1 expression, which is involved in Nrf2 activation (Zouet al., 2012).

In rat HepG2 cells, HT protects lysosomal and mitochondrialmembrane from the carcinogenic effect of ortho-phenylphenol(OPP), a fungicide and antibacterial agent used in fruits and fruitproducts, suppresses OPP-induced ROS formation, and increasesGSH level (Li et al., 2012b). In an excessive exercise (Exe) model,HT treatment inhibits the Exe-induced increase in autophagy andmitochondrial fission and the decrease in PGC-1a expression. Inaddition, HT enhances mitochondrial fusion and mitochondrialcomplex I and II activities, showing that its supplementation mayregulate mitochondrial dynamic remodeling and enhance antioxi-dant defenses, including the downregulation of mitochondrial bio-genesis and upregulation of autophagy (Feng et al., 2011). Finally,HT can induce extension of chronological lifespan in normal hu-man fibroblasts through a 3-fold increase in MnSOD activity andsuppressing also age-associated increase in mtROS levels (Sarsouret al., 2012).

2.3.4. StilbenesStilbenes are present in human diet in low quantities. Resvera-

trol (3,5,4-trihydroxystilbene) (RV) is the main representative andit has been detected in more than 70 plants species, especiallygrapevines, pines, and legumes (Soleas et al., 1997; Ungvari et al.,2011). It is also found in peanuts, soy beans, pomegranates andwine in noticeable amounts (Catalgol et al., 2012).

In its structure, RV possesses two aromatic rings bound througha methylene bridge (Fig. 9) and it can be present in cis/trans iso-forms both of which may be glucosylated. The major trans isomeris the biologically active one (Ovesná and Horváthová-Kozics,2005).

Over a couple of decades RV and its analogs have been investi-gated reporting important in vitro and in vivo beneficial effects in avariety of human disease models, such as cardio- and neuroprotec-tion, immune regulation, and cancer chemoprevention (Ferreroet al., 1998; Shigematsu et al., 2003; van Ginkel et al., 2007; Shan-kar et al., 2007). Its biological properties depend on its structuraldeterminants including the number and position of carboxylgroups, stereoisomery, intramolecular hydrogen bonding, and thepresence of double bond (Ovesná and Horváthová-Kozics, 2005;Coppa et al., 2011).

Recent studies provide evidence that RV improves endothelialfunction in rodent models of type 2 diabetes (Pearson et al.,2008; Zhang et al., 2009b) and mitigates myocardial ischemicreperfusion injury and atherosclerosis (Das and Maulik, 2006). Itscardiovascular protective potential is associated with the attenua-tion of mtROS generation (Ungvari et al., 2009), the promotion ofmitochondrial biogenesis (Csiszar et al., 2009) and the inhibitionof NF-kB (Yeung et al., 2004), among others. In human cardiomyo-cytes, pre-treatment with RV attenuates the effects of azidothymi-dine (AZT) on mtROS generation and cell death by means ofAZT-induced caspase-3 and -7 activities inhibition (Gao et al.,2011). Moreover, RV protects against AA-and iron-induced oxida-tive stress in HepG2 cells through inhibition of mitochondrialimpairment and ROS production. This cytoprotective effect is med-iated by LKB1 activation which promotes AMPK phosphorylationand therefore, mitochondrial biogenesis (Shin et al., 2009b). RValso presents neuroprotective effects against cerebral ischemia/reperfusion-induced mitochondrial dysfunctions in the hippocam-pus. In a rat middle cerebral artery occlusion model of brain ische-mia, treatment with RV significantly restores the status ofmitochondrial GSH, ATP content, activity of mitochondrial respira-tory complexes and decreases cyt c release (Yousuf et al., 2009). Onthe other hand, as a chemoprevention agent, RV is able to inhibittumor initiation, promotion, and progression of a wide variety ofmalignant cells, including leukemia (Tinhofer et al., 2001) and can-cers of the prostate (Hsieh and Wu, 1999), lung (Kim et al., 2003),stomach (Holian et al., 2002), colon (Mahyar-Roemer et al., 2001;Ito et al., 2002), liver (Delmas et al., 2000), pancreas (Ding andAdrian, 2002), and breast (Pozo-Guisado et al., 2004; Aggarwalet al., 2004). Its antitumor potential is related to activation of manydifferent mitochondrial signaling pathways of apoptosis, which arestrongly implicated in cancer progression (Pozo-Guisado et al.,2004; van Ginkel et al., 2007; Rahman et al., 2012). In Rat B103neuroblastoma cells, RV reduces the expression of the anti-apopto-tic proteins Bcl-2, Bcl-xL and Mcl-1and activates in a dose-depen-dent manner cleavage of caspase-9 and -3 via the down regulationof their respectively pro caspases. In addition, RV decreases themost important cell cycle protein cyclin D1 levels and, therefore,slows down the G1 phase leading to a dramatic reduction of cellgrowth, thus indicating the involvement of intrinsic mitochon-dria-mediated apoptotic pathway in both mechanisms (Rahmanet al., 2012). Moreover, the viability of mice SK-N-AS, NGP, andSH-SY5Y neuroblastoma cells lines also decreases in a time andconcentration-dependent manner in response to RV as a result of


DWm collapse (in whole cells and isolated mitochondria) as wellas the release of cyt c into the cytosol (van Ginkel et al., 2007).

Bcl2 down regulation is implicated in the RV induced apoptosisin MCF-7 human breast cancer cells, in which the decline in Bcl-2levels is caused by NF-kB inhibition suggesting an induction ofapoptosis even by a caspase-independent pathway (Pozo-Guisadoet al., 2004). DWm dissipation is implicated in the RV inducedapoptosis in HepG2 cells (Ma et al., 2007), human epidermoid car-cinoma A431 cells (Madan et al., 2008), T-acute lymphoblastic leu-kemia cells (Tinhofer et al., 2001) and BTT739 and T24 bladdercarcinoma cell lines (Lin et al., 2012d). In HepG2 cells the collapseof DWm is related with the MPTP opening, the concomitant releaseof cyt c and the elevation of intracellular Ca2+ necessary formitochondrial membrane depolarization (Ma et al., 2007), whilein human epidermoid carcinoma A431 cells (Madan et al., 2008),T-acute lymphoblastic leukemia cells (Tinhofer et al., 2001) andBTT739 and T24 bladder carcinoma cell lines (Lin et al., 2012d)the breakdown of DWm is accompanied by an over production ofROS and the activation of caspase-9 and caspase-3. The activationof caspase-3 by RV is also responsible for the apoptosis andtherefore the inhibition of cell proliferation in human colon cancerHT-29 cells (Juan et al., 2008). Finally, RV induces apoptosis inASTC-a-1 lung adenocarcinoma cells (i) via translocation of AIFfrom the mitochondria to the nucleus and to a lesser extent (ii)via caspases-9- and -3-dependent intrinsic mitochondrial apopto-tic pathway (Zhang et al., 2011).

2.3.5. LignansLignans are produced by oxidative dimerization of two phenyl-

propane units; they are mainly present in the free form, while theirglycoside derivatives are only a minor form. Their main dietarysource is linseed (Adlercreutz and Mazur, 1997). However, thereare still no available data in peer-reviewed literature about theireffects on mitochondria.

3. Conclusions

Recently research studies have demonstrated that many bioac-tive compounds present in foods may be used alone or in combina-tion with conventional therapeutic agents to prevent the onset andto control the development of several diseases. The protection ofmitochondrial function by these dietary agents may be importantin explaining their beneficial effects on health. In this review, theinvolvement of some dietary compounds in mitochondrial functionand dysfunction has been discussed, with special attention to bio-genesis and to the regulation of apoptotic pathways.

Mitochondria play pivotal roles in numerous cellular processesinvolved in cell life and death and the regulation of these processesis implicated in several metabolic, degenerative and hyperprolifer-ative diseases. Mitochondria also exhibit many structural and func-tional features which differ from other cellular compartments,making them a potential target for a broad range of diverse deliv-ery systems, with therapeutic purposes. Targeting mitochondriawith antioxidant agents is of primary interest for their antiagingproperties, with some of the main applications focused on neuro-degenerative diseases and cardioprotection, while pro-oxidantand cytotoxic agents are under investigation for cancer therapy.The differences in mitochondrial function between normal andcancer cells may offer a unique potential for the design of antican-cer agents that deliver mitochondrial targeting compounds toselectively kill cancer cells.

But even though mitochondria present numerous potential tar-gets and the knowledge about functional characteristics in relationto diseases is continuously increasing, investigating the action ofbioactive compounds on mitochondrial functionality is still a novel

field for scientific research. The use of novel dietary compoundsthat directly affect the mitochondrial functionality have the poten-tial to emerge as a key platform technology for the next generationof functional foods, nutraceuticals and drugs.

Conflict of Interest

The authors declare that there are no conflicts of interest.

Transparency Document

The Transparency document associated with this article can befound in the online version.

Acknowledgment

The authors would like to thank to Ms. Monica Glebocki forextensive editing of the manuscript.

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