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Investigation of Mutations in Nuclear Genes That Affect the Atp Synthase Russell Dsouza Wayne State University

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Investigation of Mutations in Nuclear Genes That Affect the Atp Synthase Russell Dsouza Wayne State University Wayne State University Wayne State University Dissertations 1-1-2016 Investigation Of Mutations In Nuclear Genes That Affect The Atp Synthase Russell Dsouza Wayne State University, Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Biochemistry Commons, and the Molecular Biology Commons Recommended Citation Dsouza, Russell, "Investigation Of Mutations In Nuclear Genes That Affect The tA p Synthase" (2016). Wayne State University Dissertations. 1526. https://digitalcommons.wayne.edu/oa_dissertations/1526 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. INVESTIGATION OF MUTATIONS IN NUCLEAR GENES THAT AFFECT THE ATP SYNTHASE by RUSSELL L. D’SOUZA DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2016 MAJOR: BIOCHEMISTRY & MOLECULAR BIOLOGY Approved By: Advisor Date © COPYRIGHT BY RUSSELL L. D’SOUZA 2016 All Rights Reserved DEDICATION I dedicate my dissertation work to my family. My deepest gratitude to my parents, Raymond and Emma D’Souza, whose constant support has helped me pursue my dreams. My brother Reuben, who has always been there by my side. I also dedicate this thesis to my wife, Jayshree Bhakta, who has always been there for me during the difficult times at graduate school. I will always appreciate all that she’s done for me and for all the encouragement. She’s been the best cheerleader in my life. Finally, a special thanks to my best friend Joe D. Klavitter and his wife Jessica, for all the help and the much needed love. You guys truly are the best and thank you for being there for me. ii ACKNOWLEDGEMENTS I want to take this opportunity to thank several people without whom this thesis would have never been written and this journey never completed. I am highly indebted to my Ph.D. supervisor, Dr. Sharon Ackerman, for accepting me in the laboratory as a graduate student and for introducing me to the world of mitochondrial biology, a field that I was not too familiar with. It was because of her scientific guidance, cheerful enthusiasm, and her ability to ask the right scientific questions that I was able to complete my doctoral studies in a respectable manner. The one virtue that I would want to emulate from Dr. Ackerman is to pay attention to detail, whether it be scientific experiments or other aspects of my graduate training. All of the knowledge that I possess with regards to mitochondrial biology, I owe it to her. She will continue to inspire me in many ways. I wish to express gratitude to my dissertation committee members, Dr. David Evans, Dr. Domenico Gatti, and Dr. Miriam Greenberg. Their thoughts and suggestions at the various committee meetings has been highly invaluable and has nurtured me to be a better graduate student. I cannot thank them enough and will always be indebted to them. I would also like to thank everybody at the Department of Biochemistry and Molecular Biology, for accepting me into their graduate program and for their constant help and support. My deepest gratitude to the departmental graduate committee for helping me out in all of the difficult situations. A big thank you to the administrative staff, without whom the graduate paperwork would have never been in order. Finally, I would like to thank the IBS, my family and the many friends that have been with me throughout this incredible journey. iii TABLE OF CONTENTS DEDICATION............................................................................................................................... ii ACKNOWLEDGEMENTS ........................................................................................................ iii LIST OF TABLES ....................................................................................................................... vi LIST OF FIGURES .................................................................................................................... vii CHAPTER 1: INTRODUCTION ................................................................................................ 1 1.1 General Introduction .......................................................................................................... 1 1.2 Advantages of the yeast model to study mitochondrial energy metabolism .................. 2 1.3 ATP Synthase structure ...................................................................................................... 5 1.4 Assembly of the mitochondrial ATP synthase .................................................................. 8 1.5 Mechanism of ATP synthesis ........................................................................................... 10 1.6 Human pathologies linked to the mitochondrial ATP synthase ................................... 13 CHAPTER 2: MATERIALS AND METHODS ...................................................................... 18 Cells and Media. ...................................................................................................................... 18 Preparation of yeast mitochondria ........................................................................................ 18 ATPase assays. ......................................................................................................................... 19 Extraction of F 1Fo from mitochondria. ................................................................................. 20 Step sucrose centrifugation analysis of F 1-ATPase subunits. .............................................. 20 Linear sucrose centrifugation analysis of soluble F1Fo. ...................................................... 21 Western blotting analysis. ....................................................................................................... 22 Yeast transformations. ............................................................................................................ 23 Lactate dehydrogenase (LDH) assay. .................................................................................... 24 iv CHAPTER 3: CHARACTERIZATION OF MUTATIONS IN NUCLEAR GENES ENCODING THE aa aa -SUBUNIT OR bb bb -SUBUNIT OF YEAST MITOCHONDRIAL F 1 .... 26 Summary .................................................................................................................................. 26 Results ...................................................................................................................................... 29 Discussion ................................................................................................................................. 44 CHAPTER 4: ACCOUNTING FOR POLYMORPHISMS IN THE HUMAN ATP12 GENE (ATPAF2 ) THAT AFFECTS F 1 BIOGENESIS ....................................................................... 55 Summary .................................................................................................................................. 55 Results and discussion ............................................................................................................. 56 CHAPTER 5: THE N-TERMINAL DOMAINS OF ATP11P ................................................ 60 Summary .................................................................................................................................. 60 Results and Discussion ............................................................................................................ 62 CHAPTER 6: SCOPE OF THE STUDY AND LIMITATIONS ........................................... 66 REFERENCES ............................................................................................................................ 69 ABSTRACT ................................................................................................................................. 82 AUTOBIOGRAPHICAL STATEMENT ................................................................................. 84 v LIST OF TABLES Table 1. Subunit composition of human, yeast, and Escherichia coli ATP synthase. .................... 6 Table 2. ATPase activities of atp1 mutants. ................................................................................. 30 Table 3. ATPase activities of atp2 mutants. ................................................................................. 31 Table 4. Mutations in the a subunit of yeast F 1. .......................................................................... 44 Table 5. Mutations in the b subunit of yeast F 1. .......................................................................... 45 Table 6. ATPase activities of yeast producing plasmid-borne Atpaf2p. ...................................... 57 Table 7. ATPase activities of yeast producing plasmid-borne Atp11p variants. .......................... 63 vi LIST OF FIGURES Figure 1. The chemiosmotic model .........................................................................................2 Figure 2. Cartoons of the yeast mitochondrial ATP synthase .................................................5 Figure 3. Model of ATP synthase assembly in yeast mitochondria ........................................9 Figure 4. The mechanism of ATP synthesis ..........................................................................12 Figure 5A. Mutant genes cloned and sequences from atp1 and atp2 yeast strains belonging
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