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Novel Functions of Mitochondrial Proteins in Health and Disease NOVEL FUNCTIONS OF MITOCHONDRIAL PROTEINS IN HEALTH AND DISEASE A Dissertation Presented to the Faculty of the Weill Cornell Graduate School of Medical Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Suzanne R. Burstein June 2017 © 2017 Suzanne R. Burstein NOVEL FUNCTIONS OF MITOCHONDRIAL PROTEINS IN HEALTH AND DISEASE Suzanne R. Burstein, Ph.D. Cornell University 2017 Mitochondria are organelles critical for many cellular functions including energy production, ion homeostasis, cellular protein trafficking, and apoptosis induction. While the mitochondrial protein machinery that performs these roles has been studied for many years, the functions of many of these proteins have not been fully elucidated. This dissertation is focused on understanding the functions of two proteins in mitochondria, and their involvement in disease. We describe a novel function for estrogen receptor beta (ERβ) in brain mitochondria. We find that ERβ modulates cyclophilin D-dependent mitochondrial permeability transition (MPT) in brain. MPT is critical in cell death following brain injuries, such as stroke. Based on sex differences in ERβ modulation of MPT, we suggest that it may contribute to sex differences in cellular responses to ischemia. We also explore the protein CHCHD10, a mitochondrial protein with yet unknown function. This protein is of particular interest, as its mutations have been recently associated with familial myopathy and neurodegenerative diseases, such as ALS. We find that CHCHD10 binds to its homolog CHCHD2, and both of these proteins bind to the mitochondrial protein P32. Transient silencing of CHCHD10 expression in HEK293 cells triggers the induction of mitochondria-dependent apoptosis. We also generated and began to characterize the first CHCHD10 knockout mouse model. Data from the cellular and mouse models suggest different yet similar roles for CHCHD10 and CHCHD2 in mitochondria. Uncovering these functions and understanding the pathways that these proteins participate in is critical to understanding of basic biology, but also of the pathophysiology of disease, as the brain relies heavily on mitochondria, and mitochondrial dysfunction occurs in many neurodegenerative diseases. BIOGRAPHICAL SKETCH Suzanne R. Burstein was raised in Livingston, NJ and attended Livingston High School. She received her undergraduate degree from Lehigh University, where she completed a thesis project as part of the Eckardt Scholars Program in the lab of Dr. Colin Saldanha, Ph.D. There she studied sex differences in the response to brain injury in songbirds under the supervision of Dr. Kelli Adams Duncan, Ph.D., and became interested in further exploring cellular mechanisms underlying brain diseases. She enrolled in the Neuroscience program at Weill Cornell Graduate School of Medical Sciences, and joined the laboratory of Giovanni Manfredi, M.D. Ph.D. in the Feil Family Brain and Mind Research Institute, where she has been studying the role of mitochondrial dysfunction in neurodegenerative disease and stroke. iii DEDICATION Dedicated to Hyun Jeong Kim iv ACKNOWLEDGEMENTS First, I would like to thank my mentor, Dr. Giovanni Manfredi for supporting me in becoming an independent scientist and critical thinker, and for being an excellent role model. I am extremely grateful for the current and past members of the Manfredi lab, and the entire “MitoLab”, who have taught me everything that I know about mitochondria and have become wonderful friends. In particular, the experiments described in this work would not have been possible without the expertise of Dr. Hyun Jeong Kim, Dr. Anatoly Starkov, Dr. Liping Qian, Dr. Ping Zhou, Dr. Federica Valsecchi, and Dr. Hibiki Kawamata. Thank you to my thesis committee: Dr. Gary Gibson, Dr. Teresa Milner, and Dr. Anatoly Starkov, for their mentorship and support. I would also like to thank our collaborators at external institutions: Dr. Antoni Barrientos and Dr. Myriam Bourens at University of Miami, Dr. Cathleen Lutz at The Jackson Laboratories, and Dr. Doris Germain and Dr. Amanjot Riar at Mount Sinai School of Medicine. I must also thank the Weill Cornell Electron Microscopy Core (Dr. Leona Cohen-Gould), the Neuroanatomy EM Core (Dr. Teresa Milner), and the Cornell University Proteomics Core (Dr. Sheng Zhang). This work was made possible by my funding source, NIH F31 pre-doctoral fellowship NS090715. I would like to thank my peers and faculty members in the graduate school and neuroscience program for making this experience so rewarding. Finally, I would also like to thank my incredible partner in crime, parents, sister, and my family and friends for supporting me throughout graduate school and always. v TABLE OF CONTENTS BIOGRAPHICAL SKETCH ............................................................................... iii DEDICATION .................................................................................................. iv ACKNOWLEDGEMENTS ................................................................................. v LIST OF FIGURES .......................................................................................... ix LIST OF ABBREVIATIONS ............................................................................. xii 1. INTRODUCTION ....................................................................................... 1 1.1. Mitochondrial structure and function ................................................... 1 1.1.1. Mitochondrial structure .................................................................. 1 1.1.2. Oxidative phosphorylation ............................................................. 2 1.1.3. Mitochondrial calcium handling ..................................................... 3 1.2. Role of mitochondria in brain diseases ............................................... 5 1.2.1. Mitochondria in neurodegeneration ............................................... 5 1.2.2. Mitochondria in stroke ................................................................... 7 1.3. Aims of thesis work ............................................................................. 8 2. ESTROGEN RECEPTOR BETA MODULATES PERMEABILITY TRANSITION IN BRAIN MITOCHONDRIA ......................................... 10 2.1. Abstract ............................................................................................ 10 2.2. Introduction ....................................................................................... 11 2.2.1. Sex differences in stroke ............................................................. 11 2.2.2. Mitochondrial permeability transition ........................................... 11 2.2.3. Estrogen and estrogen receptors (ERs) in mitochondria ............ 13 2.3. Materials and methods ..................................................................... 14 2.3.1. Animals ....................................................................................... 14 2.3.2. Preparation of mitochondria from brain ....................................... 14 2.3.3. Calcium capacity and membrane potential measurements ......... 15 2.3.4. Western blot ................................................................................ 17 2.3.5. Hippocampal slice culture preparation and oxygen glucose deprivation .................................................................................. 17 2.3.6. Cell culture, transfection, and FLAG co-immunoprecipitation ..... 18 vi 2.3.7. Protein extraction, digestion and Tandem Mass Tag (TMT) labeling ....................................................................................... 19 2.3.8. Nano-scale reverse phase chromatography and tandem mass spectrometry (nanoLC-MS/MS) .................................................. 20 2.3.9. OSCP co-immunoprecipitation .................................................... 22 2.4. Results ............................................................................................. 22 2.4.1. Sex difference in brain mitochondria calcium capacity depends on CypD ........................................................................................... 22 2.4.2. ER modulates brain MPT in a CypD-dependent manner .......... 25 2.4.3. ERKO does not affect mitochondrial calcium-related protein expression or bioenergetics ........................................................ 29 2.4.4. ERβKO and CypD inhibition decrease cell death in female hippocampal slices exposed to oxygen glucose deprivation ....... 31 2.4.5. ER interacts with mitochondrial proteins in an estrogen- dependent manner ...................................................................... 33 2.5. Discussion ........................................................................................ 37 3. FUNCTION OF MITOCHONDRIAL PROTEIN CHCHD10....................... 43 3.1. Abstract ............................................................................................ 43 3.2. Introduction ....................................................................................... 44 3.2.1. Mutations in CHCHD10 in disease.............................................. 44 3.2.2. Twin CX9C proteins ..................................................................... 47 3.3. Material and Methods ....................................................................... 51 3.3.1. Animals ....................................................................................... 51 3.3.2. Cell culture .................................................................................. 52 3.3.3.
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