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THE FUNCTIONAL SIGNIFICANCE of MITOCHONDRIAL SUPERCOMPLEXES in C. ELEGANS by WICHIT SUTHAMMARAK Submitted in Partial Fulfillment

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THE FUNCTIONAL SIGNIFICANCE of MITOCHONDRIAL SUPERCOMPLEXES in C. ELEGANS by WICHIT SUTHAMMARAK Submitted in Partial Fulfillment THE FUNCTIONAL SIGNIFICANCE OF MITOCHONDRIAL SUPERCOMPLEXES in C. ELEGANS by WICHIT SUTHAMMARAK Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Drs. Margaret M. Sedensky & Philip G. Morgan Department of Genetics CASE WESTERN RESERVE UNIVERSITY January, 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Dedicated to my family, my teachers and all of my beloved ones for their love and support ii ACKNOWLEDGEMENTS My advanced academic journey began 5 years ago on the opposite side of the world. I traveled to the United States from Thailand in search of a better understanding of science so that one day I can return to my homeland and apply the knowledge and experience I have gained to improve the lives of those affected by sickness and disease yet unanswered by science. Ultimately, I hoped to make the academic transition into the scholarly community by proving myself through scientific research and understanding so that I can make a meaningful contribution to both the scientific and medical communities. The following dissertation would not have been possible without the help, support, and guidance of a lot of people both near and far. I wish to thank all who have aided me in one way or another on this long yet rewarding journey. My sincerest thanks and appreciation goes to my advisors Philip Morgan and Margaret Sedensky. By introduction of Dr. Chanin Limwongse and Dr. Shawn McCandless, I was given the opportunity to work with two intelligent and gracious individuals. They treated me with great respect and provided me with a nurturing and open work environment where I could speak my mind and share my ideas. They have also instilled in me the qualities of being a good scientist and thinker. Without their insightful scientific advice, guidance and support the completion of this project would not be possible. I would also like to thank them for having provided me with many opportunities to present my work at prominent conferences and speaking events. I am extremely fortunate to have been iii blessed with the opportunity to have known and work with these two great individuals. I would like to thank my committee members Dr. Charles Hoppel, Dr. Peter Harte, Dr. Shawn McCandless and Dr. Hua Lou for their guidance over the years. They have offered me invaluable advice that challenged my way of thinking. Their support and guidance has shaped me to become a better scientist and for that I am truly grateful. My appreciation also extends to my lab colleagues, both past and present. Thanks to Dr. Marni Falk for her scientific discussion and project planning. Dr. Bernhard Kayser for giving me helpful technical advice, sharing his tremendous knowledge about mitochondria, and for showing me that mitochondria really respire. Dr. Louise Steel for helping me correct the English in many of my writings. Julie Rosenjack for her sense of humor and teaching me everyday English. Thanks to Judith Preston for teaching me many lab techniques, especially how to isolate intact mitochondria from worms, and for the delicious cookies. Toni Portman, Katrina Elsaesser, Beatrice Predoi, Qiao-yun Jiang, Melinda Hubbard, Yu-Ying Yang, Ching-Chun Yang and Vinod Singaram for all your help in the lab. The collaborative efforts by these individuals are also much appreciated. Hiral Patel and David Kehres from Dr. Hoppel’s laboratory for their excellent technical assistance. Dr. Michael Kinter and Belinda Willard from Cleveland for their input and advice, and Dr. Andrew Bauman and colleagues from Dr. Eugene Kolker’s laboratory in Seattle for the mass spectrometric analysis of my BNGs. iv On a personal level, special thanks goes to my family for their relentless love and support. Since youth, my parents have stressed the importance of getting a good education to my siblings and I. Although my dad is no long with us, I know he would be proud to see that I have lived up to his words. For my mom, I express special thanks and admiration for a woman who devoted most of her life to the care of her children and family. Her unwavering love and support is beyond anything I could ever express or describe in words. Above all, I am truly grateful for the greatest gift my parents have ever given me—life. I love you both wholeheartedly mom and dad. I would like to thank Dr. Bundhit Tantiwongosi, my best friend, for offering his help and guidance when I first moved to the United States. My transition from Thailand to the United States would not have been as smooth if it weren’t for all his help. Thank you for all your help, guidance, and support through all these years. There are a few more people that I would like to thank for their contributions to my life. First is Ms. Ratree Rengsirikul, my favorite high school biology teacher. Ms. Ratree instilled in me the fundamental traits of a good scientist—curiosity and observance. She made me realize that if we want to see nature the way it really is, we have to look at it through science. Second is Ms. Srijit Tungpong, my high school mathematics teacher. She treated me like her own son and helped me overcome personal difficulties and, until this day, still offers her love and support to me. Third is Dr. Patcharee Lertrit, my supervisor and the person who introduced me to the world of mitochondrial research. Last v but not least, Ms. Rungnapa Sriwilai (P Aied) an excellent technician in Dr. Lertrit’s laboratory who taught me good laboratory techniques. Finally, I would like to thank all of my friends both in Thailand and the U.S. They have supported me through both good and bad times and because of them, my life is more vibrant and meaningful. I am thankful their presence in my life—past, present, and future. vi TABLE OF CONTENTS Dedication………………………………………………………………………………..ii Acknowledgements……………………………………………………………………..iii Table of Contents…………………………………………………………………....…vii List of Figures and Tables……………………………………………………………xiv Abstract……………………………………………………………………………...…xvii Chapter 1: Introduction 1 1.1. Mitochondrial respiratory chain complexes (MRC)………………...2 1.1.1. Structure and function...…………………………………………2 • Complex I (NADH-ubiquinone oxidoreductase) • Complex II (succinate-ubiquinone oxidoreductase) • Complex III (Ubiquinone-cytochrome c oxidoreductase) • Complex IV (cytochrome c oxidase) • Complex V (ATP synthase, F1F0-ATPase) 1.1.2. Oxidative phosphorylation………………………….………….10 1.2. Structural organization of respiratory chain complexes..............11 1.2.1. Fluid-state model……………………………………………….11 • Lateral diffusion-random collision • Ubiquinone pool behavior 1.2.2. Solid-state model……………………………………………….13 • Structural identification of respiratory supercomplex • Metabolic flux control analysis vii • Respiring mitochondrial supercomplexes 1.3 Implications of the mitochondrial supercomplex……………….…17 1.3.1. Functional advantage of supercomplexes…………………..18 • Possible mechanisms of enhanced respiratory chain function by supercomplexes • Supercomplex organization may prevent excessive mitochondrial reactive oxygen species (ROS) production 1.3.2. Assembly and stability of complex I………………………….20 1.3.3. Decline of mitochondrial supercomplexes in impaired respiratory chain function in mice and humans…………….21 • Supercomplex instability due to cardiolipin deficiency • BCS1L mutations disrupt complex III and supercomplex formation, causing Bjornstad and GRACILE syndromes • Cytochrome b mutations and combined complex I/III deficiency • Complex IV defect and combined complex I/IV deficiency • Supercomplex dysfunction in heart failure 1.4. C. elegans as a model to study the function of mitochondrial supercomplexes…………………………………………………..…....26 1.4.1. isp-1(qm150)…….……………………………………………...27 1.4.2. isp-1(qm150);ctb-1(qm189)..………………………………….28 1.4.3. Complex IV deficient C. elegans…..…………….……………29 viii 1.5. Conclusion……………………………………………………………….30 1.6. Specific Aims……………………………………………………..……..31 1.7. Figures…………………………………………...……………………….33 1.8. References……………………………………………………………….46 Chapter 2: The effects of COX IV- and COX Va-RNAi knockdowns on______ whole animal phenotypes, supercomplex function and respiratory________ chain___ function in C. elegans ____ _____ 57 2.1. Introduction……………………………………………………………...58 2.2. Results………………………………………………….…………………61 2.2.1. The effects of COX IV- and COX Va-RNAi knockdowns on whole animal phenotypes……..…………..….……..…….61 2.2.2. Efficacy of RNAi knockdown…………………………..………61 2.2.3. The effects of COX IV- and COX Va-RNAi knockdowns on respiratory chain function.……………....….....……......…61 • Oxidative phosphorylation capacity • Electron transport chain function 2.2.4. The effects of COX IV- and COX Va-RNAi knockdowns on supercomplex formation……….…………….…………...63 • Supercomplex organization in C. elegans mitochondria • COX IV and COX Va knockdowns altered supercomplex profile • Complex I formation was unchanged in COX IV and ix COX Va worms 2.3. Discussion………………………………………………………………..66
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