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Identification and Characterization of Novel Genes Involved in Cytochrome Identification and characterization of novel genes involved in cytochrome c oxidase deficiencies Woranontee Weraarpachai Department of Human Genetics McGill University, Montreal October 2011 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Ph.D. ©Woranontee Weraarpachai, 2011 1 Table of Contents Acknowledgements ................................................................................................. 5 Abstract ................................................................................................................... 7 Abstract (French) .................................................................................................... 9 Contributions of Authors ...................................................................................... 12 Abbreviations ........................................................................................................ 14 General Introduction ............................................................................................. 19 Introduction ........................................................................................................... 20 Part 1: Oxidative Phosphorylation .................................................................... 20 Part 2: Mitochondrial Genome.......................................................................... 22 Mitochondrial DNA structure and organization ........................................... 22 Mitochondrial DNA replication .................................................................... 26 Mitochondrial DNA transcription ................................................................. 27 Mitochondrial translation .............................................................................. 29 Part 3: Human diseases due to mitochondrial translation defect ...................... 38 Part 4: Complex IV or cytochrome c oxidase (COX) ....................................... 43 COX structure and function .......................................................................... 43 2 Assembly of COX ......................................................................................... 45 COX deficiency ............................................................................................ 52 Thesis outline ........................................................................................................ 57 Chapter 1: Mutation in TACO1, a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh Syndrome ................................... 60 Abstract ............................................................................................................. 61 Results and Discussion ..................................................................................... 62 Materials and Methods ...................................................................................... 69 Figure Legends.................................................................................................. 80 Figures............................................................................................................... 86 Chapter 2: Mutations in C12orf62, a factor that couples COX I synthesis to cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis ............................. 101 Abstract ........................................................................................................... 102 Introduction ..................................................................................................... 103 Results ............................................................................................................. 105 Discussion ....................................................................................................... 114 Materials and Methods .................................................................................... 118 Figure Legends................................................................................................ 130 3 Figures............................................................................................................. 136 General Discussion ............................................................................................. 147 References ........................................................................................................... 159 Appendix ............................................................................................................. 179 4 Acknowledgements My Ph.D. thesis and my Ph.D. life would not be successful without these people: I would like to give a big thank you to Prof. Eric Shoubridge for his guidance and support throughout my graduate studies, his enthusiasm is very contagious and he has always been a source of new and interesting ideas. Having a good supervisor is very important and thanks to Eric, my love for doing research has but grown over the years. Next I would like to express my gratitude to the other members of the lab past and present who have always been around if I needed help and made the lab a fun and enjoyable place that I never would like to leave. In no particular order I would like to thank Hana Antonicka for her teachings of lab techniques and for always being there with insightful advice about my project and my thesis; Florin Sasarman for being such a good teacher of the translation assay and for the time he took to discuss my project and my thesis with me; Olga Zurita, Tamiko Nishimura and Lissiene Silva Neiva for being the best companions both in and outside the lab; Timothy Johns for making my life in the lab easier, for the localization experiments, and generally having an answer for everything; Neil Webb for his help with the size exclusion experiment; Isabelle Thiffault for her translation skills; Vincent Paupe, Alex Janer, Stephen Fung, Steven Salomon who make the Shoubridge lab the awesome place that it is; Scot Leary for teaching me the COX assay, and Timothy Wai and Brendan Battersby who were always there with more information than I could ask for. Thanks to my advisory committee, Prof. David Rosenblatt and Prof. Greg Brown for their advice and suggestions during the committee meetings. 5 I would also like to thank the Thai government for the scholarship I received. My special thanks to my loving parents in Thailand, Manu and Jintana, and my brother, Jirasak who despite the distance have always been there for me. I also thank the other members of my family and friends both in Thailand and Canada who in times of need have never let me down. Finally, my best friend and husband, Pira, with whom I shared both the stressful and happy moments of this journey. 6 Abstract In mitochondria, ATP is generated by oxidative phosphorylation (OXPHOS), a process that requires five multimeric enzyme complexes. Electrons are passed along the first four enzyme complexes (complex I-IV) that make up the mitochondria respiratory chain, releasing energy that is stored in the form of a proton gradient across the mitochondrial inner membrane, and is subsequently used by the ATP synthase (complex V) to produce ATP. Complex IV or cytochrome c oxidase (COX) is the terminal enzyme in the mitochondrial respiratory chain, catalyzing the oxidation of cytochrome c by molecular oxygen. It contains 13 structural subunits in mammals, 3 of which are encoded by mitochondrial DNA. Cytochrome c oxidase deficiencies can be caused by mutations in either mitochondrial or nuclear DNA. COX deficiency can result from mutations in the structural subunits or factors necessary for the assembly of the enzyme complex. In this thesis, two novel genes mutated in two subjects with COX deficiency have been identified. First, we identified a specific defect in the synthesis of the mtDNA-encoded COX subunit 1 (COX I) in a pedigree segregating late-onset Leigh Syndrome and COX deficiency. We mapped the defect to chromosome 17q by microcell-mediated chromosome transfer and identified a homozygous single base pair insertion causing a premature stop in CCDC44, renamed TACO1 for translational activator of COX I. TACO1 is a member of a large family of hypothetical proteins containing a conserved DUF28 domain that localizes to the mitochondrial matrix. Expression of the wild-type cDNA restored TACO1 protein and rescued the translation defect. TACO1 is the first specific mitochondrial translational activator identified in mammals. Respiratory competence, mitochondrial translation and COX activity were normal in yeast strain 7 deleted for the orthologue YGR021w, suggesting that TACO1 has evolved a novel function in mammalian mitochondrial translation. Secondly, we studied a family in which the subject presented with severe congenital lactic acidosis and dysmorphic features associated with a COX assembly defect and a specific decrease in the synthesis of COX I. Using a combination of microcell mediated chromosome transfer, homozygosity mapping, and transcript profiling we mapped the gene defect to chromosome 12, and identified a homozygous missense mutation causing an amino acid change from methionine to isoleucine in C12orf62, a gene apparently restricted to the vertebrate lineage. Expression of the wild-type cDNA restored C12orf62 protein levels, and rescued the COX I synthesis and COX assembly defect. C12orf62 is a very small (6 kDa), uncharacterized, single transmembrane protein that localizes to mitochondria. COX I, II and IV subunits co-immunoprecipitated with an epitope-tagged version of
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