Mitochondria (eBook)

Dr. Stephen W. Schaffer is a professor at the University of South Alabama. He is a member of the editorial board of Molecular and Cellular Biochemistry. Dr. M.-Saadeh Suleiman is a professor at the University of Bristol, UK. His research includes investigating the role of metabolites and ionic species in myocardial protection, with special emphasis on amino acids, mitochondria, Ca2+ loading and reactive oxygen species.

Preface 6
Contents 10
Mitochondrial Metabolism 12
Regulation of Mitochondrial Respiration in Heart Muscle 13
1.1. Introduction 13
1.2. Heart Muscle Mitochondria 14
1.3. The Respiratory Chain 14
1.4. ATP Synthesis 16
1.5. Metabolite Translocation in the Inner Membrane. 18
1.6. Mitochondrial Redox Enzymes of Intermediary Metabolism Having Inner Membrane Ubiquinone as Electron Acceptor 18
1.7. Levels of Regulation of Electron Transport in the Mitochondrion 19
1.8. Substrate Level Regulation of Supply of Reducing Equivalents for the Respiratory Chain 20
1.9. Respiratory Chain Regulation 23
1.10. Concluding Remarks 29
Regulation of Fatty Acid Oxidation of the Heart 36
2.1. Introduction 36
2.2. Fatty Acid Supply to the Cardiomyocyte 37
2.3. Fatty Acid Uptake 39
2.4. Cytosolic Transport and Activation of Fatty Acids 42
2.5. Triacylglycerol as a Source of Fatty Acids 44
2.6. Regulation of Fatty Acid Transport into the Mitochondria 44
2.7. Regulation of - Oxidation 48
2.8. Interregulation of Carbohydrate and Fatty Acid Metabolism 50
2.9. Transcriptional Control of Fatty Acid Oxidation Enzymes 50
2.10. Alterations in Fatty Acid Oxidation in Disease 53
2.11. Fatty Acid Oxidation in the Ischemic and Reperfused Heart and Optimization of Fatty Acid Oxidation as a Therapeutic Approach to Treat Ischemic Heart Disease 55
2.12. Conclusions 57
Regulation of Mitochondrial Fuel Handling by the Peroxisome Proliferator- Activated Receptors 72
3.1. Introduction 72
3.2. PPARs: General Function in Relation to Tissue Distribution 73
3.3. PPARs: Domain Structure and Regulation of Transcriptional Activity 74
3.4. Pharmacological PPAR Ligands 76
3.5. Physiological PPAR Ligands 77
3.6. The Role of PPAR in the Regulation of Fuel Handling 78
3.7. Regulation of Lipid Storage by PPAR 84
3.8. The Role of PPAR in the Regulation of Oxidative Metabolism 86
3.9. PGC-1: an Enhancer of Mitochondrial Function and Biogenesis 88
3.10. Dysregulation of PPARs and PGC-1 in Disease States 90
3.11. Concluding Remarks 92
Molecular Structure of the Mitochondrial Citrate Transport Protein 105
4.1. Introduction 105
4.2. Identification of Residues that Comprise the Citrate Translocation Pathway 107
4.3. Construction of a Three-Dimensional Model of the CTP 113
4.4. Evaluation of CTP Functional Data in the Context of the Three- Dimensional CTP Homology Model 114
4.5. Criteria for Identification of Residues Involved in Substrate Binding Versus those Involved in Other Aspects of the Transport Mechanism 117
4.6. The Location of the Monomer-Monomer Interface in Homodimeric Mitochondrial Transporters 118
4.7. Perspectives and Future Directions 121
Regulation of Pyruvate and Amino Acid Metabolism 125
5.1. Introduction 125
5.2. Metabolism of Amino Acids via Pyruvate Dehydrogenase 125
5.3. Regulation of Pyruvate Dehydrogenase Complex 133
5.4. Branched-Chain Amino Acid Dehydrogenase 143
5.5. Summary 151
Amino Acids and the Mitochondria 159
6.1. Introduction and Summary 159
6.2. Amino Acid Transport Across the Mitochondrial Inner Membrane 159
6.3. Amino Acid Metabolism in the Mitochondria Under Normal Conditions 162
6.4. Amino Acids in Mitochondria Under Pathological Conditions 165
The Dynamic Nature of the Mitochondria 175
Mechanotransduction of Shear-Stress at the Mitochondria 176
7.1. Mechanotransduction of Shear–Stress 176
7.2. Mitochondrial Mechanotransduction 178
7.3. Conclusions 186
Mitochondria as Initiators of Cell Signaling 189
Formation of Reactive Oxygen Species in Mitochondria 190
8.1. Mitochondrial Sources of Reactive Oxygen Species 190
8.2. Relative Reactivity of Various Reactive Oxygen Species 192
8.3. Mitochondrial Antioxidant Defenses 193
8.4. Physiological and Pathological Scenarios Associated with Mitochondrial Reactive Oxygen Species Metabolism 195
8.5. Mitochondrial Oxidative Stress and Aging 197
8.6. Conclusions 198
Mitochondrial Calcium: Role in the Normal and Ischaemic/ Reperfused Myocardium 202
9.1. Introduction 202
9.2. Physiological Role of Mitochondrial [ Ca2+] 203
9.3. Role of Mitochondrial Ca2+ in Ischaemia/ Reperfusion Injury 213
9.4. Therapeutic Implications 218
Mitochondrial Ion Channels 226
10.1. Introduction 226
10.2. Fast Ion Movements Across the Inner Membrane 227
10.3. Physiological Roles of Mitochondrial Ion Channels 228
10.4. Protective K+ Channels 229
10.5. Sarcolemmal KATP 230
10.6. Mitochondrial KATP 230
10.7. Mitochondrial KCa 232
10.8. Channels Activated by Metabolic Stress 233
10.9. PTP or Not PTP? 234
10.10. IMAC 235
10.11. Molecular Targets 236
10.12. Conclusions 237
Mitochondria as Initiators of Cell Death 244
The Mitochondrial Permeability Transition Pore – from Molecular Mechanism to Reperfusion Injury and Cardioprotection 245
11.1. Introduction 245
11.2. The Discovery of the MPTP 246
11.3. The Consequences of MPTP Opening (Reviewed in Halestrap et al. 2004 Halestrap et al. 2002)
11.4. Factors that Regulate the MPTP (Reviewed in Halestrap and Brenner 2003 Halestrap et al. 2004
11.5. The Molecular Mechanism of the MPTP 248
11.6. The Role of the Mitochondrial Permeability Transition in Reperfusion Injury 255
11.7. The MPTP as A Target for Protecting Hearts from Reperfusion Injury. 257
11.8. The Mitochondrial Permeability Transition Pore and Apoptosis 264
11.9. Conclusions 265
The Apoptotic Mitochondrial Pathway – Modulators, Interventions and Clinical Implications 274
12.1. An Overall View of Cardiac Apoptotic Cell Death 274
12.2. The Mitochondrial Apoptotic Pathway 275
12.3. Stimulators of Apoptosis 279
12.4. Strategies for Preventing Cardiac Apoptotic Cell Death 283
12.5. Conclusion 286
The Role of Mitochondria in Necrosis Following Myocardial Ischemia- Reperfusion 294
13.1. Introduction 294
13.2. Mitochondrial and Oncosis 295
13.3. Oncotic Versus Apoptotic Death During Ischemia and Reperfusion 298
13.4. Mitochondria and Cardioprotection 300
13.5. Summary 301
Mitochondria as Modulators of Cell Death 305
Mitochondria and Their Role in Ischemia/ Reperfusion Injury 306
14.1. Myocardial Ischemia 306
14.2. Preconditioning the Heart 306
14.3. Trigger, Ischemic, and Reperfusion Phases 308
14.4. The Role of Mitochondria During Ischemia 309
14.5. Function of mKATP 312
14.6. Mitochondrial Permeability Transition Pore ( mPTP) 315
Mitochondrial DNA Damage and Repair 324
15.1. Mitochondrial Genome Overview 324
15.2. Drugs, Toxins, Oxidative Stress and Other Hazards in the Life of mtDNA 326
15.3. Endogenous Sources of ROS Pose a Risk of Oxidative Damage to mtDNA 327
15.4. Oxidative Damage to mtDNA 329
15.5. Mitochondrial DNA Damage, Mutations and Disease 331
15.6. Repair of DNA Damage in Mammalian Mitochondria 332
15.7. Base Excision Repair (BER) Pathway in Mitochondria 333
15.8. DNA-Glycosylases in Mitochondria 335
15.9. DNA Polymerase 337
15.10. Mitochondrial DNA Ligase 338
15.11. Modulation of mtDNA Repair In Vivo 338
15.12. Conclusions 339
Index 349