Mitochondria

Immo E. Scheffler, PhD, is Professor in the Division of Biology (Molecular Biology Section) at the University of California, San Diego. In addition to this well-received book, Dr. Scheffler has more than 100 original publications in scientific literature and has written numerous book chapters.

Preface xi

Preface to First Edition xv

1 History 1

References 6

2 Evolutionary Origin of Mitochondria 7

References 15

3 Structure and Morphology. Integration into the Cell 18

3.1 Structure and Morphology 19

3.2 Integration into the Cell 30

3.2.1 Distribution in the Cytosol 30

3.2.2 Interaction with Cytoskeleton 34

3.3 The Dynamics of Mitochondrial Morphology 37

3.3.1 Mitochondrial Shape Changes 37

3.3.1.1 Fission 40

3.3.1.2 Fusion 42

3.3.2 Distribution During Cell Division 46

3.3.3 During Cell Differentiation 51

3.3.4 Turnover and Degradation 54

3.3.5 Mitochondrial Alterations in Apoptosis 55

3.3.6 Unsolved Problems for the Future 55

References 56

4 Biogenesis of Mitochondria 60

4.1 The Mitochondrial Genome 61

4.1.1 Introduction 61

4.1.2 The Mitochondrial Genome in Metazoans 63

4.1.3 The Mitochondrial Genome in Plants 68

4.1.4 The Mitochondrial Genome in Fungi 72

4.1.5 The Mitochondrial Genome in Kinetoplastid Protozoa 75

4.1.6 Mitochondrial Plasmids 79

4.1.6.1 Fungal Senescence 80

4.1.6.2 Phytopathogenicity 81

4.1.6.3 Cytoplasmic Male Sterility (CMS) 81

4.2 Nuclear Genes Encoding Mitochondrial Proteins 81

4.2.1 Enzymes Required for Maintenance and Expression of the Mitochondrial Genome 82

4.2.2 Nucleo-mitochondrial Interactions 85

4.2.2.1 Introduction 85

4.2.2.2 In Yeast Saccharomyces cerevisiae 86

4.2.2.3 Regulation of Nuclear Respiratory Genes in Mammalian Cells 91

4.2.2.4 Co-evolution of Nuclear and Mitochondrial Genomes 95

4.3 Replication and Maintenance of Mitochondrial DNA 96

4.3.1 DNA Replication in Mammalian Mitochondria 96

4.3.2 mtDNA Repair in Mammalian Mitochondria 104

4.3.3 Recombination in Mammalian Mitochondria 105

4.3.4 mtDNA Maintenance and Replication in Other Organisms 105

4.4 Transcription of Mitochondrial DNA–RNA Metabolism 105

4.4.1 Transcription in Mammalian Mitochondria 105

4.4.2 Transcription of mtDNA in the Yeast Saccharomyces cerevisiae 111

4.4.3 Transcription of mtDNA in Plant Mitochondria 111

4.4.4 Transcriptional Termination 113

4.4.5 RNA Processing in Mitochondria 113

4.4.6 RNA Editing in Kinetoplastid Protozoa 116

4.4.7 Editing in Plant Mitochondria 121

4.4.8 Control of mRNA Levels by Turnover 123

4.5 Translation of Mitochondrial mRNAs 126

4.5.1 Introduction 126

4.5.2 Codon Usage and tRNA Structure 126

4.5.3 Mitochondrial Ribosomes 128

4.5.4 Cis-Acting Elements 132

4.5.5 Translation Factors 133

4.6 Protein Import into Mitochondria 141

4.6.1 Mitochondrial Targeting of Proteins 141

4.6.2 The Protein Import Machinery of Mitochondria 145

4.7 Import of Transfer RNA into Mitochondria 152

4.8 Regulated Protein Degradation in Mitochondria 153

References 156

5 Mitochondrial Electron Transfer and Oxidative Phosphorylation 168

5.1 Historical Introduction 169

5.2 The Electron Transport Chain 173

5.2.1 The Biochemical Components 173

5.2.2 Physical Separation of the Complexes of the ETC 179

5.2.2.1 Biochemical Fractionations 179

5.2.2.2 Supercomplexes 182

5.2.3 Introduction to Bioenergetics 184

5.2.4 Complex I 185

5.2.5 Complex II 195

5.2.5.1 Nuclear Versus Mitochondrial Location of Complex II Genes 200

5.2.6 Complex III 202

5.2.7 Complex IV 210

5.2.8 The Assembly of the Electron Transport Chain Complexes 220

5.3 Electron Transport in Other Organisms 224

5.3.1 NAD(P)H Dehydrogenases 224

5.3.2 A Cyanide-Insensitive Electron Pathway 225

5.3.3 NADH Oxidation in Yeasts 226

5.3.4 Energy Metabolism and NADH Oxidation in Trypanosomes 227

5.4 The Chemiosmotic Hypothesis 228

5.4.1 The Mitchell Hypothesis 228

5.4.2 The Q Cycle 237

5.4.3 Probing the Mitochondrial Membrane Potential with Fluorescent Dyes 239

5.5 ATP Synthase (F1F0-ATPase) 244

5.5.1 Introduction 244

5.5.2 X-Ray Structure 247

5.5.3 ATP Synthesis and Catalytic Mechanisms 249

5.5.4 The F0 Subcomplex and Proton Flow 253

5.5.5 Assembly of Complex V and Dimerization 257

5.6 Control of Respiration and Oxidative Phosphorylation 259

5.6.1 General Considerations 259

5.6.1.1 The Role of Substrates 261

5.6.2 The Uncoupling Proteins in Warm-Blooded Animals 266

5.6.3 Uncoupling in Other Organisms 271

5.6.3.1 In Saccharomyces cerevisiae 271

5.6.3.2 In Plants 271

5.7 Reactive Oxygen Species 272

5.8 Nitric Oxide (NO) 277

5.9 The Role of Specific Lipids 279

References 281

6 Metabolic Pathways Inside Mitochondria 298

6.1 Introduction 299

6.2 The Krebs Cycle 299

6.3 Fatty Acid Metabolism 304

6.4 The Urea Cycle 309

6.5 Biosynthesis of Heme 309

6.6 Cardiolipin and Lipid Biosynthesis/Metabolism 314

6.7 Biosynthesis of Ubiquinol (Coenzyme Q) 319

6.8 Biosynthesis of Fe–S Centers 324

6.9 Transport of Small Solutes into and out of Mitochondria 329

6.9.1 Introduction 329

6.9.2 Porin Alias VDAC 330

6.9.3 The ADP/ATP Translocator 331

6.9.4 The Mitochondrial Carrier Protein Family 334

6.9.5 Cation Transport 335

6.9.5.1 Transport of Calcium and Its Physiological Role 337

6.9.6 The Mitochondrial Permeability Transition 339

References 341

7 Mitochondrial Mutations and Disease 345

7.1 General Introduction 346

7.2 In Cell Culture 348

7.2.1 Mitochondrial Mutations in Microorganisms 348

7.2.2 Mitochondrial Mutations in Mammalian Cells in Culture 350

7.3 Molecular Genetics of Human Mitochondrial Diseases 354

7.3.1 Introduction 354

7.3.2 Maternal Versus Sporadic Inheritance 355

7.3.3 Mapping mtDNA Deletions/Rearrangements 358

7.3.4 mtDNA Point Mutations and Maternal Inheritance 359

7.3.5 Mitochondria and Oogenesis 362

7.3.6 Clinical Aspects of Mitochondrial DNA Mutations 366

7.3.6.1 MtDNA Deletions: Kearns–Sayre Syndrome and Pearson Syndrome 367

7.3.6.2 Familial Mitochondrial DNA Depletion 369

7.3.6.3 Point Mutations 369

7.3.7 Nuclear Mutations and Mitochondrial Disease 373

7.3.7.1 Defective Electron Transport Chain 373

7.3.7.2 MtDNA Maintenance and Replication 375

7.3.7.3 Friedreich’s Ataxia 376

7.3.7.4 Deafness and Dystonia Syndrome (Mohr–Tranebjaerg Syndrome) 376

7.3.8 Conclusion 377

7.4 Mitochondrial DNA and Aging 377

7.4.1 Introduction 377

7.4.2 Accumulation of mtDNA Damage and Normal Aging 380

7.4.3 Neurodegenerative Diseases 383

7.4.3.1 Parkinson’s Disease 384

7.4.3.2 Alzheimer’s Disease 386

7.4.3.3 Huntington’s Disease 387

7.4.3.4 Amyotrophic Lateral Sclerosis (ALS) 389

7.5 Mitochondria and Apoptosis 389

7.6 Fungal Senescence 398

7.7 Cytoplasmic Male Sterility in Plants 400

References 404

8 Mitochondrial DNA Sequencing and Anthropology 417

8.1 Introduction 418

8.2 Human Evolution 419

8.3 Primate Evolution 426

8.4 Human Y Chromosome Variation 428

8.5 Forensic Applications 430

8.6 Future Challenges 434

References 434

9 Mitochondria and Pharmacology 437

9.1 Introduction 437

References 438

Index 441