Carla M. Koehler Matthias F. Bauer

MitochondrialFunctionand Biogenesis

Mitochondrial genome evolution : the origin of mitochondria and o feukaryotes I

Rachel B. Bevan and B . Franz LangAbstract t1 Introduction I2 Evolution of mitochondrial genomes and genes : anything is possible 2

2 .1 The perplexing diversity of mitochondrial genome architecture 32 .2 Unusual mitochondrial gene structure and gene expression 52 .3 Past and current gene loss and gene emigration from th emitochondrial to the nuclear genome 72 .4 Immigration of genes to mitochondria, and horizontal genetransfer among plant mitochondrial genomes 1 12 .5 Possible mechanisms of gene migration 1 3

3 Mitochondrial genome diversity in major eukaryotic groups 1 43 .1 Animals 1 43 .2 Fungi 1 53 .3 Plants and green algae 1 63 .4 Protists 1 7

4 Value of mitochondrial sequences for phylogenetic inference 1 85 Origin and evolution of mitochondria and of the eukaryotes 1 9

5 .1 Eubacterial ancestry of mitochondria 1 95 .2 Serial endosymbiosis, or metabolic syntrophy model o fmitochondrial origin? 2 1

6 Concluding remarks 2 3Acknowledgements 25References 25Glossary 34

Mitochondrial biogenesis : Protein import into and across the outermembrane 37

Doron Rapaport and Frank E . Nargang 3 7Abstract 3 71 Targeting of mitochondrial precursor proteins from the cytosol to th emitochondria 3 72 The translocase of the outer membrane as the gate to the organelle 3 8

2 .1 Structure and composition of the TOM complex 3 82 .2 Tom40 is the most important component of the TOM complex 3 9

3 Translocation of precursors with a presequence across the TO Mcomplex 40

3 .1 Interactions of presequences with various Tom components 40

3 .2 The driving force for translocation of presequences across th eouter membrane 4 2

4 Interactions of the TOM complex with precursors containing interna ltargeting signals 4 2

4 .1 Import of inner membrane and intermembrane space proteins 4 35 Import of outer membrane proteins 4 6

5 .1 N-terminal anchored proteins 475 .2 Tail-anchored proteins 4 85 .3 0-barrel proteins 5 0

Acknowledgments 5 1References 5 1

Mitochondrial biogenesis . Protein import into and across the inne rmembrane 5 9

Sean P. Curran and Carla M. Koehler 5 9Abstract 5 91 Introduction 5 92 Targeting to the mitochondria 6 2

2 .1 Characteristics of targeting sequences 6 22 .2 Proteins localized to more than one compartment 6 3

3 The TIM23 translocon 6 33 .1 Translocon composition 6 33 .2 Energetics of the TIM23 translocon 65

4 The TIM22 translocon 674 .1 Evolution of the TIM complexes 674 .2 TIM22 translocon composition 674 .3 Soluble "tiny-Tim" proteins in the intermembrane space 684 .4 Five stages of translocation 6 9

5 Mitochondrial protein export pathways 7 16 Perspectives 72Acknowledgements 72References 7 3

Mitochondrial tRNA editing 8 1Jens Schuster and Mario Mörl 8 1

Abstract 8 11 Introduction 8 12 5'-Nucleotide replacement : restoring the acceptor stem 8 33 3'-Nucleotide addition : back to completion 8 54 Nucleotide insertion : U and C 8 85 Base conversion : processing prerequisite or identity switch 896 Perspective 92Acknowledgements 9 3References 93

Protein quality control in mitochondria and neurodegeneration i nhereditary spastic paraplegia 97

Peter Bross, Elena I . Rugarli, Giorgio Casari, and Thomas Langer 97Abstract 971 Introduction 9 72 Protein folding in mitochondria 993 Quality control of mitochondrial proteins 10 1

3 .1 Quality control of matrix proteins 1023 .2 Quality control of inner membrane proteins 10 3

4 Pathogenesis of hereditary spastic paraplegia (HSP) 10 64 .1 The pathogenic mechanism of HSP due to lack of paraplegin 10 84 .2 Disease-associated mutation in HSP60 10 94 .3 The role of impaired protein quality control in mitochondria i npathogenesis of HSP 11 1

5 Mitochondrial malfunction and axonal transport disturbances inHSP: Is there a common denominator? 11 3References 11 4

Defects in assembly of cytochrome oxidase : roles inmitochondrial disease 123

Fiona A. Punter and D. Moira Glerum 12 3Abstract 12 31 Introduction 12 32 Structure and function of cytochrome oxidase 1243 Assembly of cytochrome oxidase 124

3 .1 PET genes Involved in holoenzyme assembly 12 73 .2 Heme A biosynthesis in COX assembly 12 83 .3 Copper provision for COX assembly 1293 .4 COX assembly in human cells 13 3

4 Human cytochrome oxidase deficiency 1354 .1 Mutations in mtDNA causing COX deficiency 1364 .2 Mutations in COX assembly factor genes causing COXdeficiency 137

5 Discussion and conclusions 140Acknowledgements 14 1References 14 1

Function and dysfunction of the oxidative phosphorylation system

149Leo G . J . Nijtmans, Cristina Ugalde, Lambert P . van den Heuvel,and Jan A. M. Smeitink 149

Abstract 14 91 Introduction 14 92 The OXPHOS system 15 13 Complex I 15 2

3 .1 Complex I function 15 23 .2 Complex I structure 152

3 .3 Subunit composition 1533 .4 Prosthetic groups 15 33 .5 The core subunits 1543 .6 The accessory subunits 15 53 .7 The biogenesis of mitochondrial complex I 1563 .8 Complex I disorders 157

4 Complex lI 15 85 Complex III 1596 Complex IV 1607 Complex V 1628 Respiratory chain organisation 1639 The price of mitochondrial DNA 16410 Reactive oxygen species production of the OXHPOS system 16511 Concluding remarks 16 7Acknowledgements 167References 167

MtDNA maintenance and stability genes : MNGIE and mtDNA depletio nsyndromes 177

Michio Hirano, Ramon Marti, Maya R . Vila, Yutaka Nishigaki 17 7Abstract 17 71 Introduction 17 72 Mitochondrial DNA structure 1793 Replication of MtDNA 1794 MtDNA repair 18 15 MtDNA recombination 18 36 Mitochondrial nucleoside/nucleotide metabolism 18 37 Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) 18 58 MtDNA depletion 18 99 Conclusion 19 1Acknowledgements 19 2References 19 2Abbreviations 19 9

Protein translocation into mammalian mitochondria and its role in th edevelopment of human mitochondrial disorders 20 1

Sabine Hofmann and Matthias F . Bauer 20 1Abstract 20 11 Components and mechanisms of protein import into mammalianmitochondria 20 12 The mammalian TOM machinery 2043 The mammalian translocases of the mitochondria) inner membrane 20 7

3 .1 The TI M23 machinery 20 73 .2 The TIM22 machinery 20 9

4 The family of the small Tim proteins of intermembrane space 211

5 Mohr-Tranebjaerg syndrome is caused by a defect in a mitochondria lprotein import pathway 21 3

5 .1 Clinical presentation of the Mohr-Tranebjaerg syndrome 21 35 .2 Genetics of Mohr-Tranebjaerg syndrome 21 45 .3 Mitochondrial dysfunction in Mohr-Tranebjaerg syndrome 21 6

6 Concluding remarks 21 8Acknowledgements 21 8References 21 8

Mitochondrial fission and fusion machineries 227Lorena Griparic, Brian Head, and Alexander M . van der Bliek 227

Abstract 2271 Introduction 2272 Visualization of mitochondrial fission and fusion 2283 Mitochondrial division 229

3 .1 Role of a dynamin-related protein in mitochondrial division 2303 .2 Other proteins that contribute to mitochondria) outer membranedivision 23 1

3 .3 Mitochondrial inner membrane division 2343 .4 Mitochondrial division during apoptosis 23 5

4 Fusion between mitochondria

23 64 .1 Drosophila fuzzy onions, its yeast homologue Fzolp an dmammalian Mitofusins 23 64 .2 Mgml, a dynamin family member implicated i nmitochondrial fusion 23 84 .3 Ugol, a yeast accessory to Fzol and Mgml 24 1

4 .4 Mdm30, a possible link between mitochondrial fusion andubiquitination 2424.5 A v-SNARE and a SNAP binding protein that might affec tmitochondrial fusion 242

5 Future directions 242Acknowledgements 24 3References 243

VDAC function in a cellular context 251Michael Forte 25 1

Abstract 25 11 Introduction 25 12 VDAC channel - the basics 25 23 Genetics of mammalian VDACS 25 54 Mitochondria, VDAC, and Cat+ homeostasis 25 65 VDAC and cell death 25 86 VDAC and the permeability transition pore 26 07 Conclusions 26 1References 262

Lipid synthesis and transport in mitocltondrial biogenesis 267Dennis R . Voelker 26 7

Abstract 26 7I Introduction 26 72 Lipid composition and function 269

2 .1 Phosphol ipid structure 26 92 .2 Phosphatidylcholine 26 92 .3 Phosphatidylethanolamine 27 12 .4 Phosphatidylserine 27 12 .5 Phosphatidylglycerol 27 12 .6 Cardiolipin 27 22 .7 Other phosphol ipids 2732 .8 Sterols 275

3 Cellular lipid synthesis and the mitochondria 2753 .1 Non-mitochondrial phospholipid synthesis 27 53 .2 Mitochondrial phospholipid synthesis 27 6

4 Lipid import into mitochondria 2784 .1 Phosphatidylserine transport 2784 .2 Phosphatidylcholine transport 2804 .3 PhosphatidyIinositol transport 28 14 .4 Cardiolipin precursor transport 28 14 .5 Sterol transport 282

5 Lipid export from mitochondria 28 36 Concluding comments 285References 286

From electron transfer to cholesterol transfer ; molecular regulation o fsteroid synthesis in the mitochondrion 29 3

Colin .Iefcoate and Irina Artemenko 293Abstract 29 3I Introduction 29 32 Adrenal cortex as a cholesterol processor 29 53 Adrenal mitochondrion 29 7

3 .1 Unique functions in cholesterol transfer and regulation 29 73 .2 Unusual mitochondrial morphology and its hormonal regulation 29 9

4 Mitochondrial P450 cytochromes 3004 .1 An unusual electron shuttling mechanism 30 04 .2 Synthesis of mitochondrial steroidogenic enzymes 30 34 .3 Can regulation of cholesterol metabolism occur at the level o fcytochrome P450sec? 305

5 The StAR protein mediates cholesterol transport 30 66 StAR function mitochondrial cholesterol metabolism 30 7

6 . I StAR mediates cholesterol transport 3076 .2 StAR function in releation to StAR function 30 76 .3 Is StAR the key determinant of cholesterol metabolism toprcgnenolone? 309

6 .4 Is mitochondrial processing of p37 StAR necessary? 31 06 .5 StAR can function at the outer mitochondrial membrane 31 16 .6 StAR functions from the inner mitochondrial membrane i nhighly active mitochondria 31 36 .7 StAR import in relation to yeast mitochondrial protein impor tmachinery 3146 .8 Is there an intra-mitochondrial function of StAR? 31 6

7 Other supporting players in mitochondrial cholesterol biosynthesis 31 77 .1 PBR is essential for StAR activity 31 77 .2 Activation of StAR by mitochondrial free fatty acids 32 07 .3 Does the form of StAR mRNA contribute to regulation o fmitochondrial uptake? 32 0

8 Questions unanswered 3 2 2References 32 3

Index 331