Schaffer / Suleiman Mitochondria

The Dynamic Organelle
1. Auflage 2010
ISBN: 978-0-387-69945-5
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 2, 359 Seiten

Reihe: Advances in Biochemistry in Health and Disease

This book is indispensable to researchers in fields as diverse as Molecular Biology and Biophysics. It covers the important role that mitochondria play in a variety of biochemical spheres. It analyses how mitochondria affect metabolic pathways, how they are active in the regulation of cytosolic constituents, and their role in initiating signal pathways. Also covered are the way mitochondria help to regulate apoptosis, and how they modulate cellular hypertrophy and proliferation. It gives an overview of the emergence of mitochondria as an important regulator of cell signaling, with a particular focus on their pathophysiology.

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.

Autoren/Hrsg.

Schaffer, Stephen W.

Suleiman, M. Saadeh

Inhaltsverzeichnis

1;Preface;6
2;Contents;10
3;Mitochondrial Metabolism;12
3.1;Regulation of Mitochondrial Respiration in Heart Muscle;13
3.1.1;1.1. Introduction;13
3.1.2;1.2. Heart Muscle Mitochondria;14
3.1.3;1.3. The Respiratory Chain;14
3.1.4;1.4. ATP Synthesis;16
3.1.5;1.5. Metabolite Translocation in the Inner Membrane.;18
3.1.6;1.6. Mitochondrial Redox Enzymes of Intermediary Metabolism Having Inner Membrane Ubiquinone as Electron Acceptor;18
3.1.7;1.7. Levels of Regulation of Electron Transport in the Mitochondrion;19
3.1.8;1.8. Substrate Level Regulation of Supply of Reducing Equivalents for the Respiratory Chain;20
3.1.9;1.9. Respiratory Chain Regulation;23
3.1.10;1.10. Concluding Remarks;29
3.2;Regulation of Fatty Acid Oxidation of the Heart;36
3.2.1;2.1. Introduction;36
3.2.2;2.2. Fatty Acid Supply to the Cardiomyocyte;37
3.2.3;2.3. Fatty Acid Uptake;39
3.2.4;2.4. Cytosolic Transport and Activation of Fatty Acids;42
3.2.5;2.5. Triacylglycerol as a Source of Fatty Acids;44
3.2.6;2.6. Regulation of Fatty Acid Transport into the Mitochondria;44
3.2.7;2.7. Regulation of - Oxidation;48
3.2.8;2.8. Interregulation of Carbohydrate and Fatty Acid Metabolism;50
3.2.9;2.9. Transcriptional Control of Fatty Acid Oxidation Enzymes;50
3.2.10;2.10. Alterations in Fatty Acid Oxidation in Disease;53
3.2.11;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
3.2.12;2.12. Conclusions;57
3.3;Regulation of Mitochondrial Fuel Handling by the Peroxisome Proliferator- Activated Receptors;72
3.3.1;3.1. Introduction;72
3.3.2;3.2. PPARs: General Function in Relation to Tissue Distribution;73
3.3.3;3.3. PPARs: Domain Structure and Regulation of Transcriptional Activity;74
3.3.4;3.4. Pharmacological PPAR Ligands;76
3.3.5;3.5. Physiological PPAR Ligands;77
3.3.6;3.6. The Role of PPAR in the Regulation of Fuel Handling;78
3.3.7;3.7. Regulation of Lipid Storage by PPAR ;84
3.3.8;3.8. The Role of PPAR in the Regulation of Oxidative Metabolism;86
3.3.9;3.9. PGC-1: an Enhancer of Mitochondrial Function and Biogenesis;88
3.3.10;3.10. Dysregulation of PPARs and PGC-1 in Disease States;90
3.3.11;3.11. Concluding Remarks;92
3.4;Molecular Structure of the Mitochondrial Citrate Transport Protein;105
3.4.1;4.1. Introduction;105
3.4.2;4.2. Identification of Residues that Comprise the Citrate Translocation Pathway;107
3.4.3;4.3. Construction of a Three-Dimensional Model of the CTP;113
3.4.4;4.4. Evaluation of CTP Functional Data in the Context of the Three- Dimensional CTP Homology Model;114
3.4.5;4.5. Criteria for Identification of Residues Involved in Substrate Binding Versus those Involved in Other Aspects of the Transport Mechanism;117
3.4.6;4.6. The Location of the Monomer-Monomer Interface in Homodimeric Mitochondrial Transporters;118
3.4.7;4.7. Perspectives and Future Directions;121
3.5;Regulation of Pyruvate and Amino Acid Metabolism;125
3.5.1;5.1. Introduction;125
3.5.2;5.2. Metabolism of Amino Acids via Pyruvate Dehydrogenase;125
3.5.3;5.3. Regulation of Pyruvate Dehydrogenase Complex;133
3.5.4;5.4. Branched-Chain Amino Acid Dehydrogenase;143
3.5.5;5.5. Summary;151
3.6;Amino Acids and the Mitochondria;159
3.6.1;6.1. Introduction and Summary;159
3.6.2;6.2. Amino Acid Transport Across the Mitochondrial Inner Membrane;159
3.6.3;6.3. Amino Acid Metabolism in the Mitochondria Under Normal Conditions;162
3.6.4;6.4. Amino Acids in Mitochondria Under Pathological Conditions;165
4;The Dynamic Nature of the Mitochondria;175
4.1;Mechanotransduction of Shear-Stress at the Mitochondria;176
4.1.1;7.1. Mechanotransduction of Shear–Stress;176
4.1.2;7.2. Mitochondrial Mechanotransduction;178
4.1.3;7.3. Conclusions;186
5;Mitochondria as Initiators of Cell Signaling;189
5.1;Formation of Reactive Oxygen Species in Mitochondria;190
5.1.1;8.1. Mitochondrial Sources of Reactive Oxygen Species;190
5.1.2;8.2. Relative Reactivity of Various Reactive Oxygen Species;192
5.1.3;8.3. Mitochondrial Antioxidant Defenses;193
5.1.4;8.4. Physiological and Pathological Scenarios Associated with Mitochondrial Reactive Oxygen Species Metabolism;195
5.1.5;8.5. Mitochondrial Oxidative Stress and Aging;197
5.1.6;8.6. Conclusions;198
5.2;Mitochondrial Calcium: Role in the Normal and Ischaemic/ Reperfused Myocardium;202
5.2.1;9.1. Introduction;202
5.2.2;9.2. Physiological Role of Mitochondrial [ Ca2+];203
5.2.3;9.3. Role of Mitochondrial Ca2+ in Ischaemia/ Reperfusion Injury;213
5.2.4;9.4. Therapeutic Implications;218
5.3;Mitochondrial Ion Channels;226
5.3.1;10.1. Introduction;226
5.3.2;10.2. Fast Ion Movements Across the Inner Membrane;227
5.3.3;10.3. Physiological Roles of Mitochondrial Ion Channels;228
5.3.4;10.4. Protective K+ Channels;229
5.3.5;10.5. Sarcolemmal KATP;230
5.3.6;10.6. Mitochondrial KATP;230
5.3.7;10.7. Mitochondrial KCa;232
5.3.8;10.8. Channels Activated by Metabolic Stress;233
5.3.9;10.9. PTP or Not PTP?;234
5.3.10;10.10. IMAC;235
5.3.11;10.11. Molecular Targets;236
5.3.12;10.12. Conclusions;237
6;Mitochondria as Initiators of Cell Death;244
6.1;The Mitochondrial Permeability Transition Pore – from Molecular Mechanism to Reperfusion Injury and Cardioprotection;245
6.1.1;11.1. Introduction;245
6.1.2;11.2. The Discovery of the MPTP;246
6.1.3;11.3. The Consequences of MPTP Opening (Reviewed in Halestrap et al. 2004; Halestrap et al. 2002);247
6.1.4;11.4. Factors that Regulate the MPTP (Reviewed in Halestrap and Brenner 2003; Halestrap et al. 2004; Halestrap et al. 2002);247
6.1.5;11.5. The Molecular Mechanism of the MPTP;248
6.1.6;11.6. The Role of the Mitochondrial Permeability Transition in Reperfusion Injury;255
6.1.7;11.7. The MPTP as A Target for Protecting Hearts from Reperfusion Injury.;257
6.1.8;11.8. The Mitochondrial Permeability Transition Pore and Apoptosis;264
6.1.9;11.9. Conclusions;265
6.2;The Apoptotic Mitochondrial Pathway – Modulators, Interventions and Clinical Implications;274
6.2.1;12.1. An Overall View of Cardiac Apoptotic Cell Death;274
6.2.2;12.2. The Mitochondrial Apoptotic Pathway;275
6.2.3;12.3. Stimulators of Apoptosis;279
6.2.4;12.4. Strategies for Preventing Cardiac Apoptotic Cell Death;283
6.2.5;12.5. Conclusion;286
6.3;The Role of Mitochondria in Necrosis Following Myocardial Ischemia- Reperfusion;294
6.3.1;13.1. Introduction;294
6.3.2;13.2. Mitochondrial and Oncosis;295
6.3.3;13.3. Oncotic Versus Apoptotic Death During Ischemia and Reperfusion;298
6.3.4;13.4. Mitochondria and Cardioprotection;300
6.3.5;13.5. Summary;301
7;Mitochondria as Modulators of Cell Death;305
7.1;Mitochondria and Their Role in Ischemia/ Reperfusion Injury;306
7.1.1;14.1. Myocardial Ischemia;306
7.1.2;14.2. Preconditioning the Heart;306
7.1.3;14.3. Trigger, Ischemic, and Reperfusion Phases;308
7.1.4;14.4. The Role of Mitochondria During Ischemia;309
7.1.5;14.5. Function of mKATP;312
7.1.6;14.6. Mitochondrial Permeability Transition Pore ( mPTP);315
7.2;Mitochondrial DNA Damage and Repair;324
7.2.1;15.1. Mitochondrial Genome Overview;324
7.2.2;15.2. Drugs, Toxins, Oxidative Stress and Other Hazards in the Life of mtDNA;326
7.2.3;15.3. Endogenous Sources of ROS Pose a Risk of Oxidative Damage to mtDNA;327
7.2.4;15.4. Oxidative Damage to mtDNA;329
7.2.5;15.5. Mitochondrial DNA Damage, Mutations and Disease;331
7.2.6;15.6. Repair of DNA Damage in Mammalian Mitochondria;332
7.2.7;15.7. Base Excision Repair (BER) Pathway in Mitochondria;333
7.2.8;15.8. DNA-Glycosylases in Mitochondria;335
7.2.9;15.9. DNA Polymerase ;337
7.2.10;15.10. Mitochondrial DNA Ligase;338
7.2.11;15.11. Modulation of mtDNA Repair In Vivo;338
7.2.12;15.12. Conclusions;339
8;Index;349