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Molecular System Bioenergetics

Energy for Life

Edited by

Valdur Saks

InnodataFile Attachment9783527621101.jpg


Edited by

Valdur Saks


Energy for Life

Edited by

Valdur Saks

The Editor

Prof. Valdur Saks

J. Fourier University

Laboratory of Bioenergetics

2280 rue de la Piscine

38041 Grenoble Cedex 9

France

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Contents

Preface XIX

List of Contributors XXI

Introduction: From the Discovery of Biological Oxidation to Molecular

System Bioenergetics 1Valdur Saks

References 6

Part I Molecular System Bioenergetics: Basic Principles, Organization, and

Dynamics of Cellular Energetics 9

1 Cellular Energy Metabolism and Integrated Oxidative

Phosphorylation 11Xavier M. Leverve, Nellie Taleux, Roland Favier, Cécile Batandier,

Dominique Detaille, Anne Devin, Eric Fontaine, and Michel Rigoulet

Abstract 111.1 Introduction 111.2 Membrane Transport and Initial Activation 131.3 Cytosolic Pathway 131.4 Mitochondrial Transport and Metabolism 151.5 Respiratory Chain and Oxidative Phosphorylation 171.6 Electron Supply 171.7 Reducing Power Shuttling Across the Mitochondrial Membrane 191.8 Electron Transfer in the Respiratory Chain: Prominent Role of

Complex I in the Regulation of the Nature of Substrate 191.9 Modulation of Oxidative Phosphorylation by Respiratory Chain

Slipping and Proton Leak 21

V

1.10 The Nature of Cellular Substrates Interferes with the Metabolic

Consequences of Uncoupling 221.11 Dynamic Supramolecular Arrangement of Respiratory Chain and

Regulation of Oxidative Phosphorylation 23References 25

2 Organization and Regulation of Mitochondrial Oxidative

Phosphorylation 29Michel Rigoulet, Arnaud Mourier, and Anne Devin

Abstract 292.1 Introduction 292.2 Oxidative Phosphorylation and the Chemiosmotic Theory 302.3 The Various Mechanisms of Energy Waste 312.3.1 Passive Leak 312.3.2 Leak Catalyzed by Uncoupling Proteins 332.3.3 The Active Leak 332.3.4 The Slipping Mechanism 352.4 Mechanisms of Coupling in Proton Pumps 362.5 Oxidative Phosphorylation Control and Regulation 382.5.1 Metabolic Control Analysis 382.5.2 Regulations 392.5.2.1 Kinetic Regulation of Mitochondrial Oxidative Phosphorylation:

Complex I Covalent cAMP-dependent Phosphorylation 392.5.2.2 Cytochrome Oxidase: An Example of Coordinate Regulation 392.6 Supramolecular Organization of the Respiratory Chain 432.6.1 Structural Data 442.6.1.1 ATP Synthase Organization 442.6.1.2 Respiratory Chain Supramolecular Organization 452.6.2 Functional Data 462.7 Conclusions 49

References 49

3 Integrated and Organized Cellular Energetic Systems: Theories of Cell

Energetics, Compartmentation, and Metabolic Channeling 59Valdur Saks, Claire Monge, Tiia Anmann, and Petras P. Dzeja

Abstract 593.1 Introduction 603.2 Theoretical Basis of Cellular Metabolism and Bioenergetics 603.2.1 Thermodynamic Laws, Energy Metabolism, and Cellular

Organization 603.2.2 Chemical and Electrochemical Potentials: Energy of Transmembrane

Transport and Metabolic Reactions 623.2.3 Non-equilibrium, Steady-state Conditions 663.2.4 Free Energy Changes and the Problem of Intracellular Organization of

Metabolism 67

VI Contents

3.2.5 Macromolecular Crowding, Heterogeneity of Diffusion,

Compartmentation, and Vectorial Metabolism 683.2.5.1 Heterogeneity of Intracellular Diffusion and Metabolic Channeling 683.2.5.2 Compartmentation Phenomenon and Vectorial Metabolism 693.3 Compartmentalized Energy Transfer and Metabolic Sensing 713.3.1 Compartmentation of Adenine Nucleotides in Cardiac Cells 713.3.2 Unitary (Modular) Organization of Energy Metabolism and

Compartmentalized Energy Transfer in Cardiac Cells 733.3.3 Functional Coupling of Mitochondrial Creatine Kinase and Adenine

Nucleotide Translocase 763.3.3.1 Kinetic Evidence of Functional Coupling 773.3.3.2 Thermodynamic Evidence of Functional Coupling 823.3.4 Heterogeneity of ADP Diffusion in Permeabilized Cells: Importance of

Structural Organization 833.3.5 Evidence for the Importance of Functional Coupling for Cell Life 883.3.6 Myofibrillar Creatine Kinase 883.3.7 Membrane-bound Creatine Kinases and Membrane Energy

Sensing 893.3.8 The Mechanism of Acute Contractile Failure of the Ischemic Heart 913.3.9 Creatine Kinase System in Brain Cells 933.3.10 Maxwell’s Demon and Organized Cellular Metabolism 94

References 97

4 On the Network Properties of Mitochondria 111Miguel A. Aon, Sonia Cortassa, and Brian O’Rourke

Abstract 1114.1 Introduction 1114.1.1 Conceptual Issues About Networks 1154.2 The Study of (Sub)Cellular Networks and the Emerging View of Cells

as Dynamic Mass Energy Information Networks 1154.3 Mitochondrial Morphodynamics 1174.4 The Key Role of Inner and Outer Membrane Ion Channels on

Mitochondrial Network Dynamics 1184.5 Mitochondrial Network Behavior Associated with Intracellular

Signaling 1204.5.1 Mitochondria as Intracellular Timekeepers 1214.6 Mitochondria as a Network of Coupled Oscillators 1234.6.1 Spatial and Temporal Aspects of Synchronization 1264.6.2 Mitochondrial Network Collapse and Scaling: A Cascade of Failures

from the Bottom Up 1264.7 Discussion 1274.7.1 What Is the Contribution of the Network View of Mitochondrial

Function? 1274.7.2 Why a Network View of Mitochondria May Contribute to

Understanding Aging and Illness 128

Contents VII

4.8 Concluding Remarks 129References 129

5 Structural Organization and Dynamics of Mitochondria in the Cells

in Vivo 137Andrey V. Kuznetsov

Abstract 1375.1 Introduction 1385.2 Intracellular Organization of Mitochondria 1395.2.1 Multiple Functions of Mitochondria in the Cells in Vivo 1395.2.2 Analysis of Mitochondrial Dynamics and Intracellular Organization in

Vivo: Confocal Fluorescent Microscopy 1395.2.3 Mitochondrial Clusters and Subpopulations, Mitochondrial

Heterogeneity, and their Physiological and Pathophysiological Roles 1405.2.4 Mitochondria as Discrete Units in Highly Differentiated Cells Versus

the Mitochondrial Interconnected Network 1435.2.5 Role of Mitochondrial Interactions with Other Intracellular Structures

for Regulating Mitochondrial and Cellular Function 1445.2.6 Tissue and Cell-type Specificity of Mitochondrial Intracellular

Organization and Dynamics 1455.3 Mitochondrial Dynamics: Regulation of Mitochondrial

Morphology 1475.3.1 Mitochondrial Shape Proteins 1485.3.2 Mitochondrial Fusion and Fission 1495.3.3 Mitochondrial Fragmentation During Apoptosis 1505.3.4 Apoptotic Control and Mitochondrial Dynamics 1515.3.5 The Importance of Spatial Mitochondrial Organization for Mediating

Lethal Ca2þ Waves 1525.4 Mitochondrial Dynamics: Mitochondrial Movement (Motility) in the

Cell 1535.4.1 Key Role of the Cytoskeleton and Specific Motor and Connector

Proteins for Mitochondrial Movement 1535.4.2 Motility of Mitochondria in Neurons 1545.5 Concluding Remarks 155

References 156

Part II Energy Transfer Networks, Metabolic Feedback Regulation, and Modeling of

Cellular Energetics 163

6 Mitochondrial VDAC and Its Complexes 165Dieter Brdiczka

Abstract 1656.1 The Role of VDAC in Controlling the Interaction of Mitochondria with

the Cytosol 166

VIII Contents

6.2 Molecular Structure and Membrane Topology of VDAC 1696.3 VDAC Conductance, Voltage Dependence, and Ion Selectivity 1696.4 The Physiological Significance of VDAC Voltage Gating 1706.5 VDAC Isoforms and Functions 1716.6 Mitochondria and Apoptosis 1726.7 VDAC and ANT May Form the Mitochondrial Permeability Transition

Pore 1726.8 Accessory MPT Pore Subunits 1736.9 ANT Knockout Studies 1736.10 The Role of VDAC in Organizing Kinases at the Mitochondrial

Surface 1746.11 Hexokinase–VDAC–ANT Complexes in Tumor Cells 1756.12 Hexokinase as a Marker Enzyme of Contact Sites 1756.13 VDAC–ANT Complexes 1766.14 VDAC–ANT Complexes Contain Cytochrome c 1766.15 VDAC Oligomerization and Cytochrome c Binding 1776.16 Possible Function of Cytochrome c in the Contact Sites 1776.17 Cholesterol and Cardiolipin Influence VDAC Structure and

Function 1796.18 The Importance of VDAC Complexes in Regulation of Energy

Metabolism and Apoptosis 1806.19 Suppression of Bax-dependent Cytochrome c Release and Permeability

Transition by Hexokinase 1816.20 Suppression of Permeability Transition and Cytochrome c Release by

Mitochondrial Creatine Kinase 1836.21 The General Importance of the Creatine Kinase System in Heart

Performance 1846.22 The Central Regulatory Role of ANT 184

References 186

7 The Phosphocreatine Circuit: Molecular and Cellular Physiology of

Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by

Creatine Supplementation 195Theo Wallimann, Malgorzata Tokarska-Schlattner, Dietbert Neumann,

Richard M. Epand, Raquel F. Epand, Robert H. Andres, Hans Rudolf Widmer,

Thorsten Hornemann, Valdur Saks, Irina Agarkova, and Uwe Schlattner

Abstract 1957.1 Phosphotransfer Enzymes: The Creatine Kinase System 1967.1.1 Microcompartments: A Principle of Life 1967.1.2 Subcellular Compartments and Microcompartments of CK 1977.1.3 Tissue-specific Expression of Creatine Kinase Isoenzymes 1997.1.4 Temporal and Spatial Buffering Functions of Creatine Kinases:

The CK–Phosphocreatine Circuit 2007.1.5 A Closer Look at CK (Micro)Compartments and High-energy

Phosphate Channeling 204

Contents IX

7.1.6 Subcellular Compartmentation of CK at the Myofibrillar M-band:

ATP Regeneration for Muscle Contraction 2077.1.7 Subcellular Localization of CK at the Sarcoplasmic Reticulum and

Plasma Membrane 2097.1.8 Subcellular Compartments of CK at the Plasma Membrane and

Functional Coupling with Naþ/Kþ-ATPase 2117.1.9 Structural and Functional Coupling of Cytosolic CK with ATP-sensitive

Kþ Channels and KCC2 2117.1.10 CK Interaction with the Golgi GM130 Protein 2127.1.11 Specific Compartments of Cytosolic CK with Insulin and Thrombin

Signaling Pathways 2137.1.12 Subcellular Compartments of CK with Glycolytic Enzymes and

Targeting of Glycolytic Multi-enzyme Complexes 2137.1.13 High-energy Phosphate Channeling by MtCK in Energy-transducing

Mitochondrial Compartments 2147.2 Creatine Kinases and Cell Pathology 2157.2.1 Mitochondrial MtCK, the Mitochondrial Permeability Transition Pore,

and Apoptosis 2157.2.2 Mitochondrial MtCK and Intramitochondrial Inclusions in

Mitochondrial Myopathy 2167.2.3 Overexpression of MtCK in Certain Malignancies 2177.3 Novel Membrane-related Functions of MtCK 2177.3.1 Transfer of Lipids by Proteins That Bridge the Inner and Outer

Mitochondrial Membrane 2187.3.2 Lipid Transfer at Contact Sites 2197.3.3 Cardiolipin Transfer and Apoptosis 2207.3.4 Cardiolipin Domains and Mitochondrial Kinases 2217.3.5 Perspectives: Relationship Between the Surface Exposure of Cardiolipin

and Expression Levels of Mitochondrial Kinases 2227.4 Exquisite Sensitivity of the Creatine Kinase System to Oxidative

Damage 2237.4.1 Molecular Damage of Creatine Kinase by Oxidative and Nitrosative

Stress 2237.4.2 Molecular Basis of Creatine Kinase Damage 2247.4.3 Functional Consequences of Oxidative Damage in Creatine

Kinase 2267.5 Enhancement of Brain Functions and Neuroprotection by Creatine

Supplementation 2267.5.1 Creatine Metabolism and Brain Energetics 2267.5.2 Disturbance of the CK System or Creatine Metabolism in the

Brain 2277.5.3 Body and Brain Creatine Metabolism 2287.5.4 Effects of Creatine on Memory, Mental Performance, and Complex

Tasks 2307.5.5 Creatine Supplementation and Neurodegenerative Diseases 230

X Contents

7.5.6 Creatine Supplementation and Acute Neurological Disorders 2337.5.7 Inborn Errors of Metabolism 2347.5.8 Psychiatric Disorders 2357.5.9 Neurorestorative Strategies 2357.5.10 Future Prospects of Creatine Supplementation as Adjuvant Therapeutic

Strategy 2367.5.11 Non-energy–related Effects of Creatine 2377.5.12 Creatine as a Safe Nutritional Supplement and Functional Food 238

References 240

8 Integration of Adenylate Kinase and Glycolytic and Glycogenolytic

Circuits in Cellular Energetics 265Petras P. Dzeja, Susan Chung, and Andre Terzic

Abstract 2658.1 Introduction 2668.2 The Adenylate Kinase Phosphotransfer System in Cell Energetics and

AMP Metabolic Signaling 2698.2.1 The Biological Role of Adenylate Kinase 2698.2.2 Adenylate Kinase Isoform-based Metabolic Network 2718.2.3 Adenylate Kinase Catalyzed b-phosphoryl Transfer and Energy

Economy 2748.2.4 Adenylate Kinase–instigated AMP Metabolic Signaling and Energy

Sensing 2768.3 Glycolysis as a Network of Phosphotransfer Circuits and Metabolite

Shuttles 2788.3.1 Glycolytic Phosphotransfer Circuits 2818.3.2 Glycolytic Pi Shuttle 2828.3.3 Glycolytic Lactate Shuttle 2838.3.4 Neural Glycolytic Network: Role in Energetics and Information

Processing 2838.4 Glycogen Energy Transfer Network: Adding a Spatial Dimension to

Glycogenolysis 2848.5 Concluding Remarks: Integration of Phosphotransfer Pathways 289

References 292

9 Signaling by AMP-activated Protein Kinase 303Dietbert Neumann, Theo Wallimann, Mark H. Rider,

Malgorzata Tokarska-Schlattner, D. Grahame Hardie, and Uwe Schlattner

Abstract 3039.1 Metabolism and Cell Signaling 3049.1.1 A Critical Role for Protein Kinase Signaling 3049.1.2 At the Interface of Energy Metabolism and Protein Kinase Signaling:

AMPK as Receptor for Cellular Energy State 3059.2 Sensing and Signaling of Cellular Energy Stress Situations 306

Contents XI

9.2.1 Why AMP Represents an Ideal Second Messenger for Reporting

Cellular Energy State 3069.2.2 A Closer Look at the Role of Creatine Kinase and Adenylate Kinase in

AMPK Activation 3109.2.3 Some Considerations on the Sensing and Signaling Properties of

AMPK 3139.3 Mammalian AMPK Is a Member of an Ancient, Conserved Protein

Kinase Family 3149.3.1 AMPK in the Eukaryotic Kinome 3149.3.2 Structure of AMPK 3149.4 Regulation of AMPK 3159.4.1 Allosteric Regulation of AMPK 3169.4.2 Regulation of AMPK by Upstream Kinases 3189.4.3 Inactivation of AMPK by Protein Phosphatases 3209.5 Signaling Downstream of AMPK 3219.5.1 Role of AMPK 3219.5.2 The AMPK Recognition Motif 3229.5.3 A Note of Caution: The Krebs–Beavo Criteria 3229.5.4 The AMPK-related Protein Kinases 3269.5.5 Multi-site/Hierarchical Phosphorylation and Convergence of Signaling

Pathways on AMPK Targets 3269.6 Conclusions and Perspectives 327

References 328

10 Developmental and Functional Consequences of Disturbed Energetic

Communication in Brain of Creatine Kinase–deficient Mice:

Understanding CK’s Role in the Fuelling of Behavior and Learning 339Femke Streijger, René in ‘t Zandt, Klaas Jan Renema, Frank Oerlemans,

Arend Heerschap, Jan Kuiper, Helma Pluk, Caroline Jost,

Ineke van der Zee, and Bé Wieringa

Abstract 33910.1 Use of Reverse Genetics to Study CK Function in Mouse Models 34010.2 Expression Distribution of Brain-type CK mRNA and Protein

Isoforms 34210.3 CK��=�� Mice Have Lower Body Weights 34710.4 31P Magnetic Resonance Spectroscopy 34810.5 Altered Brain Morphology: Involvement of the Intra-infra-pyramidal

Mossy Fiber Field in CK��=�� Mice 34910.6 CK��=�� Mice Show Impaired Spatial Learning in Wet and Dry Maze

Tests 35210.7 Cued Performance and Motor Coordination Are Normal in CK��=��

Mice 35410.8 CK��=�� Mice Show Normal Open-field Exploration and

Habituation 355

XII Contents

10.9 CK��=�� Mice Show Abnormal Thermogenesis 35610.10 Altered Acoustic Startle Reflex Response and Hearing Problems in

CK��=�� Mice 35610.11 Pentylenetetrazole-induced Seizures Occur Later in B-CK��=��

Mice 35710.12 Conclusions and Future Outlook 360

References 363

11 System Analysis of Cardiac Energetics–Excitation–Contraction Coupling:

Integration of Mitochondrial Respiration, Phosphotransfer Pathways,

Metabolic Pacing, and Substrate Supply in the Heart 367Valdur Saks, Petras P. Dzeja, Rita Guzun, Mayis K. Aliev, Marko Vendelin,

André Terzic, and Theo Wallimann

Abstract 36711.1 Introduction 36711.2 Cardiac Energetics: The Frank-Starling Law and Its Metabolic

Aspects 36811.3 Excitation–Contraction Coupling and Calcium Metabolism 37111.3.1 Excitation–Contraction Coupling 37111.3.2 The Mitochondrial Calcium Cycle 37311.4 Length-dependent Activation of Contractile System 37411.5 Integrated Phosphotransfer and Signaling Networks in Regulation of

Cellular Energy Homeostasis 37511.5.1 Evidence for the Role of MtCK in Respiration Regulation in

Permeabilized Cells in Situ 37611.5.2 In Vivo Kinetic Evidence 37911.5.3 Mathematical Modeling of Metabolic Feedback Regulation 38111.6 ‘‘Metabolic Pacing’’: Synchronization of Electrical and Mechanical

Activities With Energy Supply 38511.7 Metabolic Channeling Is Needed for Protection of the Cell from

Functional Failure, Deleterious Effects of Calcium Overload, and

Overproduction of Free Radicals 38811.8 Molecular System Analysis of Integrated Mechanisms of Regulation of

Fatty Acid and Glucose Oxidation 38911.9 Concluding Remarks and Future Directions 394

References 396

12 Principles of Mathematical Modeling and in Silico Studies of Integrated

Cellular Energetics 407Marko Vendelin, Valdur Saks, and Jüri Engelbrecht

Abstract 40712.1 Introduction 40712.2 Mathematical Modeling 40812.2.1 Basic Principles 408

Contents XIII

12.2.2 Hierarchies 40912.3 Modeling of Energy Metabolism 41012.3.1 Enzyme Kinetics 41012.3.2 Modeling of Intracellular Events 41412.3.3 Thermodynamically Consistent Models 41512.4 Interaction Between Enzymes 41712.4.1 Phenomenological Modeling 41812.4.2 Modeling the Mechanism of Functional Coupling Between MtCK and

ANT 41812.5 Linking Mechanics and Free Energy Profile 42312.5.1 Terrell Hill Formalism 42312.5.2 Actomyosin Interaction 42512.6 Concluding Remarks 427

References 429

13 Modeling Energetics of Ion Transport, Membrane Sensing and Systems

Biology of the Heart 435Satoshi Matsuoka, Hikari Jo, Masanori Kuzumoto, Ayako Takeuchi,

Ryuta Saito, and Akinori Noma

Abstract 43513.1 Introduction 43513.2 Modeling ATP-related Systems 43613.2.1 Naþ/Kþ-ATPase 43713.2.2 SERCA and PMCA 43813.2.3 Contraction 44313.2.4 ATP-sensitive Kþ Channel and L-type Ca2þ Channel 44413.2.5 Mitochondrial Oxidative Phosphorylation 44513.3 ATP Balance in the Kyoto Model 44513.4 Feedback Control and Ca2þ-dependent Regulation of Mitochondria

Function 448References 452

Part III Applied Molecular System Bioenergetics 457

14 Mitochondrial Adaptation to Exercise and Training: A Physiological

Approach 459Kent Sahlin

Abstract 45914.1 Introduction 46014.2 Control of Oxidative Phosphorylation 46014.2.1 Influence of Oxygen Availability on the Control of Oxidative

Phosphorylation 46414.3 Mitochondrial Uncoupling and Mitochondrial Efficiency 467

XIV Contents

14.4 Quantitative and Qualitative Adaptations of Mitochondria to

Training 47114.4.1 Effect of Training on Mitochondrial Quantity 47114.4.2 Effect of Training on Mitochondrial Quality 47214.5 Effect of Acute Exercise on Mitochondrial Function 47214.5.1 Effect of Strenuous Exercise on Maximal Respiration 47314.5.2 Effect of Acute Exercise on Non-coupled Respiration (State 4) and

Mitochondrial Efficiency 47314.5.3 Work Efficiency and Mitochondrial Efficiency 47414.6 Integrated View of the Role of Mitochondria in Exercise Physiology 474

References 475

15 Mitochondrial Medicine: The Central Role of Cellular Energetic

Depression and Mitochondria in Cell Pathophysiology 479Enn Seppet, Zemfira Gizatullina, Sonata Trumbeckaite, Stephan Zierz,

Frank Striggow, and Frank Norbert Gellerich

Abstract 47915.1 Introduction 48015.2 The Concept and Molecular Mechanisms of Cellular Energetic

Depression and Mitochondrial Cell Death 48315.2.1 Interaction of Mitochondria and Sarco/Endoplasmic Reticulum in

Regulation of Cytosolic Ca2þ 48615.2.2 Role of Altered Energy Compartmentation in Cellular Energetic

Depression 48715.3 Involvement of Mitochondria in Aging and Disease 48915.3.1 Mitochondria and Aging 48915.3.2 Mitochondria in Neurodegenerative Diseases 49015.3.2.1 Huntington’s Disease 49015.3.2.2 Parkinson’s Disease 49115.3.2.3 Alzheimer’s Disease 49215.3.2.4 Hypoxia 49315.3.2.5 Cancer 49515.3.2.6 Inflammation 49715.4 Detection of Mitochondrial Dysfunction by Multiple Substrate Inhibitor

Titration and Application of Metabolic Control Analysis 500References 504

16 Tumor Cell Energetic Metabolome 521Sybille Mazurek

Abstract 52116.1 Introduction 52116.2 Otto Warburg’s Discovery 52216.3 Glycolysis: A Bifunctional Pathway in Tumor Cells 522

Contents XV

16.3.1 Compartmentalization of Glycolysis in the Cytosol by the Glycolytic

Enzyme Complex 52316.3.2 Tumor Cell Characteristic Glycolytic Isoenzyme Profiles and Regulation

Mechanisms 52416.3.3 Influence of Transcription Factors and Oncoproteins 52916.4 Regeneration of Cytosolic NADþ: An Achilles Heel in the Tumor Cell

Energetic Metabolome 52916.4.1 Lactate Dehydrogenase 53016.4.2 Glycerol 3-P Shuttle 53116.4.3 Malate–Aspartate Shuttle 53116.5 Glutaminolysis: A Second Main Pillar for Energy Conversion in Tumor

Cells 53216.5.1 The Truncated Citric Acid Cycle 53216.5.2 The Glutaminolytic Pathway 53216.5.3 Energy Conversion in Glutaminolysis 53316.5.4 Advantages and Disadvantages of Glutaminolysis 53316.6 AMP: A Mediator Between Tumor Cell Energetic Metabolism and Cell

Proliferation 53416.7 The Tumor Cell Energetic Metabolome as a Tool for Tumor

Diagnosis 53516.8 The Tumor Cell Energetic Metabolome as a Target for Therapy 535

References 536

17 AMPK and the Metabolic Syndrome 541Benoit Viollet and Fabrizio Andreelli

Abstract 54117.1 Defining the Metabolic Syndrome 54117.2 Pathophysiology of the Metabolic Syndrome 54317.3 AMPK as a Strong Determinant of the Metabolic Syndrome 54417.3.1 AMPK in the Control of Whole-body Insulin Sensitivity 54617.3.2 AMPK Controls Glucose Homeostasis and Insulin Secretion 54717.3.3 AMPK Controls Lipid Metabolism 54817.3.4 AMPK and Ectopic Lipid Deposition in Tissue 54917.3.5 AMPK as a Regulator of White Adipose Tissue Physiology 54917.3.6 AMPK Alterations in Cardiovascular Pathology 55117.4 Management of the Metabolic Syndrome 55217.4.1 Management of the Metabolic Syndrome by Exercise 55317.4.2 Management of Obesity 55417.4.3 Management of Lipotoxicity 55517.4.4 Management of Glucose Homeostasis Alteration 55517.4.5 Management of Fatty Liver 55617.4.6 Management of Cardiovascular Disease 55717.5 Conclusions and Medical Perspectives 558

References 559

XVI Contents

18 A Systems Biology Perspective on Obesity and Type 2 Diabetes 571Jolita Ciapaite, Stephan J.L. Bakker, Robert J. Heine, Klaas Krab,

and Hans V. Westerhoff

Abstract 57118.1 Introduction 57218.2 Glucose Homeostasis 57218.3 Obesity in Relation to Glucose Homeostasis 57318.4 Fatty Acid–induced Insulin Resistance 57418.5 Fatty Acid–induced b-cell Dysfunction 57618.6 Type 2 Diabetes from the Systems Biology Point of View 57718.7 Metabolic Control Analysis 57918.7.1 Definitions of Metabolic Control Analysis 58018.7.2 Theorems of Metabolic Control Analysis 58218.7.3 Modular Metabolic Control Analysis 583

References 586

Index 593

Contents XVII

Preface

When Thucydides wrote his famous book The History of the Peloponnesian War inAthens in 460–400 BC, he supplied it with the following commentary: ‘‘My work

is not a piece of writing designed to meet the taste of an immediate public, but

was done to last forever.’’ We could borrow this comment for our book, whose

intention is to survey the results of more than 200 years of research in cellular

bioenergetics, from the discovery that respiration is a process of biological oxida-

tion by Lavoisier and Laplace in the 18th century, to the latest achievements of

molecular system bioenergetics in explaining the mechanistic basis of its regula-

tion. Respiration is la raison de être of cells, and a knowledge of the mechanismsassociated with biological oxidation, free energy transduction, and regulation of

cellular respiration implies understanding how cells obtain energy for life. The

scope of cellular energetics, however, is much broader than studying the mecha-

nisms involved in respiratory regulation, because all biochemical processes are

inseparable from free energy transduction, thus including the whole metabolism

and the description of all kinds of work performed by cells.

At present, the biological sciences are witnessing a radical change in para-

digms. Reductionism – which used to be the philosophical basis of biochemistry

and molecular biology, when everything from genes to proteins and organelles

were studied in their isolated state – is making way for systems biology, which

favors the study of integrated systems at all levels: cellular, organ, organism, and

population. Reductionism was justified in the initial stages of biological research,

giving a wealth of information on system components. It is timely to put them

together and analyze them in interaction, to understand the principles of func-

tioning of the whole. These paradigmatic changes also concern bioenergetics.

Unraveling the mechanisms of regulation of cellular energetics only appears to

be possible by using an integrated approach based on computational models,

which we call molecular system bioenergetics.

Not everybody, however, was taken by surprise following these paradigmatic

changes. There have been pioneers in the systemic approach to biochemistry

and metabolism. The roots of systems biology can be traced back to the works of

Pasteur, Claude Bernard, Meyerhof, Cori, and Krebs, among others, and its theo-

retical basis can be found in the work of Norbert Wiener, the founder of cyber-

netics. Regarding cellular energetics, an important line of research of metabolic

XIXXIX

networks, energy transfer, and metabolic regulation has always existed, particu-

larly emphasizing the significance of structure–function relationships for the in-

tegrated regulation of metabolic networks.

The aim of this book is to describe the ‘‘state of the art’’ of these investigations

by the authors who have been most actively committed to developing integrated

approaches to studying energy metabolism. In our pursuit we follow the histori-

cal unfolding of these developments, emphasizing the most important achieve-

ments in the area during the last 100 years. We begin with basic information

about mitochondrial structure and function and a general description of the theo-

retical bases of cellular metabolism and bioenergetics in open thermodynamic

systems, including Schrödinger’s principle of negentropy. This is followed by an

analysis of mitochondrial behavior and processes in cells, taking into account

macromolecular crowding and compartmentation phenomena. The most impor-

tant part of the book is devoted to the description of compartmentalized energy

transfer in muscle and brain cells. The experimental data gathered during the

last several decades in many laboratories allow us to explain the mechanistic

bases of two highly significant phenomena for physiological energetics: the

Frank–Starling law of the heart, related to the regulation of respiration, and acute

ischemic cardiac contractile failure. This approach explains the regulation of sub-

strate supply in the heart as well.

The last part of the book analyzes the applied aspects of cellular bioenergetics –

the problems of mitochondrial pathology, exercise physiology, cancer research,

and a new important area of research, the ‘‘metabolic syndrome’’ – related to the

medical and socioeconomic problems of modern societies. Because these dis-

eases, which are related to cellular and whole-body derailment of basic metabo-

lism, are reaching epidemic proportions in the ‘‘civilized’’ world, the regulation

of sugar and fat metabolism, once considered an old-fashioned discipline of phys-

iological biochemistry, is back in the limelight again. Amazingly, these old disci-

plines and fields of metabolic regulation often are rediscovered and uncovered by

young scientists, making it even more important to analyze the achievements of

bioenergetics in historical perspective.

This effort intends to be a useful manual and valuable reference book for a

large scientific audience, namely, in biology and medicine. We hope it will also

be a resourceful tool for undergraduate and doctoral students, post-doctoral stu-

dents, and research workers in bioenergetics, biophysics, biochemistry, cell biol-

ogy, pharmacology, physiology, pathophysiology, and medicine.

Grenoble, May 2007 Valdur Saks

XX Preface

List of Contributors

Irina Agarkova

University Hospital of Zurich

Department of Cardiovascular

Surgery Research

Rämistrasse 100

8091 Zurich

Switzerland

Mayis K. Aliev

Cardiology Research Center

Institute of Experimental

Cardiology

Laboratory of Cardiac Pathology

3rd Cherepkovskaya Street 15A

121552 Moscow

Russia

Fabrizio Andreelli

Bichat Claude Bernard Hospital

Diabetology-Endocrinology-

Nutrion Department

46 Rue Henri Huchard

75877 Paris Cedex 18

France

Robert H. Andres

University of Bern

Department of Neurosurgery

Inselspital

Freiburgerstrasse 10

3010 Bern

Switzerland

Tiia Anmann

National Institute of Chemical and

Biological Physics


Akadeemia tee 23

12618 Tallinn

Estonia

Miguel A. Aon

Johns Hopkins University

Institute of Molecular Cardiobiology

720 Rutland Avenue

1059 Ross Building

Baltimore, MD 21205

USA

Stephan J.L. Bakker

University of Groningen and

University Medical Center Groningen

Department of Internal Medicine

Hanzeplein 1

9700 RB Groningen

The Netherlands

Cécile Batandier

Université Joseph Fourier

Bioénergétique Fondamentale et

Appliquée

INSERM E-0221

BP 53X

38041 Grenoble Cedex

France

XXI

Dieter Brdiczka

University of Konstanz

Faculty of Biology

Untere Bohlstrasse 45

78465 Konstanz

Germany

Susan Chung

Mayo Clinic College of Medicine

Departments of Biochemistry and

Molecular Biology

200 First Street SW

Rochester, MN 559095

USA

Jolita Ciapaite

Vytautas Magnus University

Faculty of Nature Sciences

Centre of Environmental

Research

Vileikos 8

44404 Kaunas

Lithuania

and

VU University

Faculty of Earth and Life Sciences

Department of Molecular Cell

Physiology

Institute for Molecular Cell

Biology

De Boelelaan 1085

1081 HV Amsterdam

The Netherlands

Sonia Cortassa


Institute of Molecular

Cardiobiology

720 Rutland Avenue

1059 Ross Building

Baltimore, MD 21205

USA

Dominique Detaille



Appliquée

INSERM E-0221

BP 53X


France

Anne Devin

Université de Bordeaux 2

Institut de Biochimie et de Génétique

Cellulaires du CNRS

1 Rue Camille Saint Saëns

33077 Bordeaux Cedex

France

Petras P. Dzeja


Departments of Medicine, Molecular

Pharmacology, and Experimental

Therapeutics

Division of Cardiovascular Diseases

200 First Street SW


USA

Jüri Engelbrecht

Tallinn University of Technology

Institute of Cybernetics

Centre for Nonlinear Studies

Akadeemia tee 21

12618 Tallinn

Estonia

Raquel F. Epand

McMaster University

Department of Biochemistry and

Biomedical Sciences

Health Science Centre

1200 Main Street West

Hamilton, Ontario, L8N 3Z5

Canada

XXII List of Contributors

Richard M. Epand

McMaster University

Department of Biochemistry and

Biomedical Sciences

Health Science Centre

1200 Main Street West

Hamilton, Ontario, L8N 3Z5

Canada

Roland Favier



Appliquée

INSERM U884

BP 53X


France

Eric Fontaine



Appliquée

INSERM U884

BP 53X


France

Frank Norbert Gellerich

KeyNeurotek AG

ZENIT – Technology Park

Magdeburg

Leipziger Strasse 44

39120 Magdeburg

Germany

Zemfira Gizatullina

KeyNeurotek AG


Magdeburg


39120 Magdeburg

Germany

Rita Guzun



Appliquée

INSERM U884

BP 53X


France

D. Grahame Hardie

University of Dundee

College of Life Science

Division of Molecular Physiology

Sir James Black Centre

Dow Street

Dundee DD1 5EH

United Kingdom

Arend Heerschap

Radboud University Nijmegen

Medical Centre

Department of Radiology

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Robert J. Heine

VU University Medical Center

Department of Endocrinology

Institute for Cardiovascular Research

De Boelelaan 1117

1007 MB Amsterdam

The Netherlands

Thorsten Hornemann

University Hospital Zurich

Institute of Clinical Chemistry

Rämistrasse 100

8091 Zurich

Switzerland

List of Contributors XXIII

René in ’t Zandt


Medical Centre


P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Hikari Jo

Kyoto University

Department of Physiology and

Biophysics

Graduate School of Medicine

Yoshida-Konoe, Sakyo-ku

Kyoto 606-8501

Japan

Caroline Jost


Medical Centre

Department of Cell Biology

NCMLS 283

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Klaas Krab

VU University



Physiology


Biology

De Boelelaan 1085

1081 HV Amsterdam

The Netherlands

Jan Kuiper


Medical Centre


P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Andrey V. Kuznetsov

Innsbruck Medical University

Department of General and Transplant

Surgery

Daniel-Swarovski Research Laboratory

Innrain 66

6020 Innsbruck

Austria

Masanori Kuzumoto

Discovery Research Laboratories

Shionogi & Co., Ltd.

12-4, Sagisu 5-chome

Fukushima-ku

Osaka 553-0002

Japan

Xavier M. Leverve



Appliquée

INSERM U884

BP 53X


France

Satoshi Matsuoka

Kyoto University



Biophysics


Kyoto 606-8501

Japan

XXIV List of Contributors

Sybille Mazurek

Institute of Biochemistry and

Endocrinology

Veterinary Faculty

University of Giessen

Frankfurter Strasse 100

35392 Giessen

Germany

and

ScheBo Biotech AG

Netanyastrasse 3

35394 Giessen

Germany

Claire Monge



Appliquée

INSERM U884

BP 53X


France

Arnaud Mourier


Institut de Biochimie et de

Génétique

Cellulaires du CNRS



France

Dietbert Neumann

ETH Zurich

Hoenggerberg

Institute of Cell Biology

HPM-D24

Schafmattstrasse 18

8093 Zurich

Switzerland

Akinori Noma

Kyoto University

Graduate School Medicine


Biophysics


Kyoto 606-8501

Japan

Frank Oerlemans


Medical Centre


NCMLS 283

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Brian O’Rourke


Institute of Molecular Cardiobiology

720 Rutland Avenue

1059 Ross Building

Baltimore, MD 21205

USA

Helma Pluk


Medical Centre


NCMLS 283

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Klaas Jan Renema


Medical Centre


P.O. Box 9101

6500 HB Nijmegen

The Netherlands

List of Contributors XXV

Mark H. Rider

Christian de Duve Institute of

Cellular Pathology

Hormone and Metabolic Research

Unit

Avenue Hippocrate 75

1200 Brussels

Belgium

and

University of Louvain

Medical School

1200 Brussels

Belgium

Michel Rigoulet


Institut de Biochimie et de

Génétique

Cellulaires du CNRS



France

Kent Sahlin

GIH

Swedish School of Sport and

Health Sciences


Pharmacology

Box 5626

11486 Stockholm

Sweden

and

University of Southern Denmark

Institute of Physiology and

Clinical Biomechanics

5230 Odense

Denmark

Ryuta Saito

Discovery Technology Laboratory

Mitsubishi Pharma Corporation

1000, Kamoshida-cho, Aoba-ku

Yokohama 227-0033

Japan

Valdur Saks



Appliquée

INSERM U884

BP 53X


France

and

National Institute of Chemical and

Biological Physics


Akadeemia tee 23

12618 Tallinn

Estonia

Uwe Schlattner

ETH Zurich

Hoenggerberg


HPM-D24

8093 Zurich

Switzerland

and


Laboratoire de Bioénergétique

Fondamentale et Appliquée

INSERM U884

BP 53X


France

Enn Seppet

University of Tartu

Department of Pathophysiology

19 Ravila Street

50411 Tartu

Estonia

XXVI List of Contributors

Femke Streijger


Medical Centre


NCMLS 283

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Frank Striggow

KeyNeurotek AG


Magdeburg


39120 Magdeburg

Germany

Ayako Takeuchi

Kyoto University



Biophysics


Kyoto 606-8501

Japan

Nellie Taleux



Appliquée

INSERM E-0221

BP 53X


France

André Terzic


Departments of Medicine,

Medicinal Genetics, Molecular

Pharmacology, and Experimental

Therapeutics

200 First Street SW


USA

Malgorzata Tokarska-Schlattner


Laboratoire de Bioénergétique

Fondamentale et Appliquée

INSERM U884

BP 53X


France

Sonata Trumbeckaite

Kaunas University of Medicine

Institute for Biomedical Research

4 Eiveniu Street

50009 Kaunas

Lithuania

Ineke van der Zee


Medical Centre


NCMLS 283

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Marko Vendelin

Tallinn University of Technology

Institute of Cybernetics

Laboratory of Systems Biology

Centre for Nonlinear Studies

Akadeemia tee 21

12618 Tallinn

Estonia

Benoit Viollet

Université Paris 5

Department of Endocrinology,

Metabolism, and Cancer

Institut Cochin

INSERM U567, CNRS UMR 8104

24 Rue du Faubourg Saint-Jacques

75014 Paris

France

List of Contributors XXVII

Theo Wallimann

ETH Zurich

Hoenggerberg


HPM-D24

Schafmattstrasse 18

8093 Zurich

Switzerland

Hans V. Westerhoff

VU University



Physiology


Biology

De Boelelaan 1085

1081 HV Amsterdam

The Netherlands

and

The University of Manchester

Manchester Centre for Integrative

Systems Biology, MIB

Sackville Street

Manchester M60 1QD

United Kingdom

Hans Rudolf Widmer

University of Bern

Department of Neurosurgery

Inselspital

Freiburgerstrasse 10

3010 Bern

Switzerland

Bé Wieringa


Medical Centre


NCMLS 283

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Stephan Zierz

Universität Halle/Wittenberg

Neurologische Klinik und Poliklinik

der Martin-Luther-Universität

06097 Halle/Saale

Germany

XXVIII List of Contributors

molecular system bioenergetics · system bioenergetics 1 valdur saks references 6 part i molecular...

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