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On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2020-04-13 On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA Sabouny, Rasha Sabouny, R. (2020). On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA (Unpublished doctoral thesis). University of Calgary, Calgary, AB. http://hdl.handle.net/1880/111801 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA by Rasha Sabouny A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOCHEMISTRY AND MOLECULAR BIOLOGY CALGARY, ALBERTA APRIL, 2020 © Rasha Sabouny 2020 Abstract Mitochondria are functionally and structurally fascinating organelles, well known for their role as the cellular powerhouse. Unlike other membrane bound organelles, mitochondria maintain their own genome (mtDNA), which is present in hundreds of copies per cell, packaged into nucleo-protein structures known as nucleoids. An important regulator of mitochondrial function is their dynamic nature, whereby ongoing fusion and fission events remodel mitochondrial network morphology and influence mitochondrial activity. Dynamic fusion and fission forces are also key for distributing mtDNA nucleoids throughout mitochondrial networks and the maintenance of mtDNA copy number. Notably, mutations in core mitochondrial fusion (MFN2, OPA1) and fission (DRP1) proteins lead to enlarged nucleoids, mtDNA depletion and cause severe mitochondrial diseases. However, we do not completely understand how or why these processes are important for mtDNA. Additionally, there remains a lot to be learned about the molecular regulators mediating fusion and fission of mitochondrial networks. This project set out to characterize novel mitochondrial fusion and fission factors and further understand how defective fusion and fission regulation influence mtDNA dynamics. The work outlined in this thesis showcases three nuclear-encoded mitochondrial disease genes (FBXL4, MSTO1 & MYH14) implicated as regulators of mitochondrial morphology and shown to be important for mtDNA regulation. Firstly, this work characterizes an established mtDNA depletion syndrome gene, FBXL4 and provides the first evidence that FBXL4 protein is a mitochondrial fusion regulator. Secondly, MSTO1, a recently described cytosolic fusion regulator, is highlighted as perturbations in MSTO1 pro-fusion activity gives rise to mtDNA depletion and altered nucleoid distribution. Lastly, the largely uncharacterized non-muscle myosin protein, NMIIC, encoded by MYH14, is highlighted as novel component of the mitochondrial fission machinery. A pathogenic mutation in MYH14 causing peripheral neuropathy reduces fission and adversely affects the distribution of mtDNA nucleoids, ii particularly at the cell periphery. Through genetic and pharmacological rescue approaches to restore mitochondrial network morphology in these models, this work contributes to our understanding on the interplay between fusion and fission dynamics and mtDNA maintenance. iii Preface This thesis is written in a manuscript-based format, as such there may be some redundancy in the information included in introduction sections. In order to minimize repetition in materials & methods sections, a separate chapter (Chapter 2) was added compiling details on all methodology used to produce this work, and respective methods sections were removed from main chapters. A final bibliography section was added combining all referenced literature. Chapter 1 includes sections from a literature review published as Sabouny R & Shutt TE. “Mitochondrial Fission and Fusion are Reciprocally Regulated”. 2020. Trends in Biochemical Sciences. (https://doi.org/10.1016/j.tibs.2020.03.009) Chapter 3 of this thesis was published as Sabouny R, Wong R, Lee-Glover L, Greenway SC, Sinasac D, Care4Rare Canada Consortium, Khan A, Shutt TE. “Characterization of the C584R variant in the mtDNA depletion syndrome gene FBXL4, reveals a novel role for FBXL4 as a regulator of mitochondrial fusion”. 2019. BBA Molecular Basis of Disease;1865(11):165536 Chapter 4 has been published as Donkervoort S*, Sabouny R*, Yun P, Gauquelin L, Chao KR, Hu Y, Al Khatib I, Töpf A, Mohassel P, Cummings BB, Kaur R, Saade D, Moore SA, Waddell LB, Farrar MA, Goodrich JK, Uapinyoying P, Chan SHS, Javed A, Leach ME, Karachunski P, Dalton J, Medne L, Harper A, Thompson C, Thiffault I, Specht S, Lamont RE, Saunders C, Racher H, Bernier FP, Mowat D, Witting N, Vissing J, Hanson R, Coffman KA, Hainlen M, Parboosingh JS, Carnevale A, Yoon G, Schnur RE; Care4Rare Canada Consortium, Boycott KM, Mah JK, Straub V, Foley AR, Innes AM, Bönnemann CG, Shutt TE. “MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement”. 2019. Acta Neuropathologica, doi: 10.1007/s00401-019-02059-z (*co-first authors) iv Chapter 5 includes data that were published as Almutawa W, Smith C, Sabouny R, Smit RB, Zhao T, Wong R, Lee-Glover L, Desrochers-Goyette J, Ilamathi HS; Care4Rare Canada Consortium, Suchowersky O, Germain M, Mains PE, Parboosingh JS, Pfeffer G, Innes AM, Shutt TE. “The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy”. 2019. EBioMedicine; 45:379-392. v Acknowledgements Firstly, I would like to thank my supervisor Dr. Tim Shutt for introducing me to the world of mitochondria! Tim, I am very grateful to your unconditional support, your contagious enthusiasm for science and your kind spirit. Thank you for mentoring me to be a great scientist and a better person. I am very fortunate to have joined your lab and if time goes back, I would do it all over again in a heartbeat! To my colleagues at the Shutt Lab, Iman Al Khatib, Tian Zhao, Erik Fraunberger, Dr. Walaa Al Mutawa, Sandra Nishikawa, Dr. Govinda Sharma, Dr. Mezbah Uddin, Laurie Lee- Glover, Alon Gilad, Rachel Wong, Liam Aleksiuk and Rafa Abbas. Thank you for making everyday fun and always finding a reason to ‘celebrate’. I will miss the Shutt Lab shenanigans! Iman, thank you for reminding me that ‘finished is better than perfect!’ and for showing me that with determination it is possible to be Super-Mom-Super-Scientist! Tian, thank you for looking out for me and sharing lab snacks and free food location updates! Erik, Christmas carols still do not sound the same and I am sure this statement will be true 20 years from now. Thank you for bringing your lightheartedness and laughter to many lab mission-impossibles! And to my awesome summer students, Laurie, Alon, Rachel, Rafa and Liam, thank you for making this whole journey more worthwhile, I loved every moment of working with you, learning from you and teaching you! Ms Lisa Mesluk, thank you for being an absolute star, helping me navigate administrative hurdles, find mysteriously missing lab orders and taking care of business! My committee members, Dr. David Schriemer and Dr. David Sinasac, thank you for your support throughout my PhD, mentoring me to be a good researcher and always reminding me to keep the big picture in mind! Also, thanks to my internal examiner Dr. Jennifer Corcoran, and my external examiner Dr. Suzanne Hoppins. I am truly grateful to your support amidst the vi COVID-19 global crisis. I am hoping that this will be an amusing memory to share down the road. This work would not have been possible without our collaborations with Dr. Aneal Khan, Dr. Michael Innes, Dr. Steve Greenway, Dr. Gerald Pfeffer, Dr. Jillian Parboosingh and the Medical Genetics team at Alberta Children’s Hospital. Additionally, thanks to our collaborators at NIH, Dr. Sandra Donkervoort and Dr. Carsten Bönnemann, and at SickKids, Dr. Grace Yoon, and their respective teams, for the opportunity to work together. Thank you all for providing us with patient fibroblasts and sharing your expertise to study many mitochondrial disease cases. My friends, thank you for putting up with me despite the many times I cancelled our plans, dragged you to the lab on weekends or made you wait while I wrap up experiments. Thank you for keeping me sane! And finally, my family, thank you for constantly reminding me that there is life outside the lab and ‘trying’ not to ask how many more years till I graduate and when I would get a real job. Thank you for loving and supporting me, I really could not have gotten this far without you. vii Dedication To my parents, Hala & Kadry, my siblings, Abdullah & Farah. Thank you for believing in me. “I solemnly swear that I am up to no good.” – Moony, Wormtail, Padfoot & Prongs viii Table of Contents Abstract....................................................................................................................................... ii Preface ...................................................................................................................................... iv Acknowledgements .................................................................................................................... vi Dedication ...............................................................................................................................
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