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Final Copy 2020 01 23 Seag This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Seager, Richard A Title: Investigating the role of SUMOylation of Mitochondrial Fission Factor in Mitochondrial Dynamics General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. Investigating the role of SUMOylation of Mitochondrial Fission Factor in Mitochondrial Dynamics Richard A. Seager A dissertation submitted to the University of Bristol in accordance with the requirements for award of the degree of Doctor of Philosophy in the School of Biochemistry, Faculty of Life Sciences September 2019 Word Count 45,216 Abstract The dynamic nature of mitochondrial fusion and fission allows rapid adaptability to changing metabolic demands and stress to restore homeostasis. The principal fission protein is the cytosolic GTPase dynamin related protein-1 (DRP1), which binds to the outer membrane receptors mitochondrial fission protein 1 (Fis1), mitochondrial dynamics proteins (MiD49/51) and mitochondrial fission factor (MFF). MFF is the predominant pro-fission receptor, whereas MiD proteins sequester inactive DRP1 and form a trimeric complex of DRP1-MiD-MFF. The fusion and fission machinery are subject to multiple forms of post- translational modifications (PTM) to regulate mitochondrial function. AMPK phosphorylation of MFF at S155/S172 promotes fission under energetic stress, and parkin-mediated ubiquitination promotes mitophagy. The small ubiquitin-like modifier (SUMO) isoform SUMO-1 promotes DRP1 recruitment, whereas SUMO- 2/3-DRP1 represses fission during oxygen/glucose deprivation (OGD). I present a novel finding that MFF is SUMOylated at K151, which is enhanced by phosphorylation at S155. A SUMO-deficient MFF mutant (K151R) has reduced ubiquitination, which occurs at a separate site to K151, suggesting SUMOylation promotes ubiquitination. The K151R mutant has reduced binding to DRP1, but surprisingly, the MFF phospho-null and phospho-mimetic mutants also have reduced binding. SUMOylation of MFF reduces the association of MFF with MiD proteins, and I present a model whereby the degree of SUMOylation mediates the ratio of MiD in the DRP1-MiD-MFF complex. Intriguingly, expression of the K151R mutant in primary neurons enhances dendritic mitochondrial size and reduces density, with no effect on axonal mitochondria, suggesting differential compartment-specific regulation and/or roles of MFF SUMOylation. My data indicate that MFF SUMOylation is enhanced following OGD and is required for DRP1 binding following mitochondrial depolarisation. Taken together, these results demonstrate that there is substantial crosstalk between the PTMs of MFF, and MFF SUMOylation is required to regulate the fine-tuning of mitochondrial dynamics under basal conditions and is also involved in the stress response. i Author’s declaration I declare that the work in this dissertation was carried out in accordance with the requirements of the University's Regulations and Code of Practice for Research Degree Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, the work is the candidate's own work. Work done in collaboration with, or with the assistance of, others, is indicated as such. Any views expressed in the dissertation are those of the author. SIGNED: ............................................................. DATE: .......................... ii Acknowledgements First and foremost, I would like to thank my supervisor Jeremy, for giving me the opportunity to undertake my PhD in your lab and for all the support and encouragement along the way. Also, thank you for the freedom you gave me to pursue my own ideas, no matter how superfluous they were! My thanks go to Suko, Kev and Dan, for help, advice, liking good music and for all the neurons! I will miss the science (and philosophical) discussions. Particularly, my thanks go to Kev, for his assistance, dedication and teaching me almost everything during this PhD. I learnt so much from you, and this PhD would not have been possible were it not for your help. If ever I become as good a scientist as you, I know I would have made it. To everyone else in the Henley/Hanley labs, past and present, thank you for making my PhD a fulfilling and enjoyable time. A special thanks goes to Dr Luis, for all the laughs, lunch breaks and craziness. I would like to thank all those who have provided advice and assistance along the way; to Dr Stephen Cross for image analysis, your macros saved me a lot of time and headaches! Professor Jeremy Tavaré for the AMPK cells, Professors David Chan and Michael Schrader for supplying the MEF cells. My thanks also go to Mr. Paul Murphy for advice and reagents for the deubiquitination in vitro experiment, to Dr Nadia Rawlings for help with OGD experiments, and to Dr Laura Lee for trying to muddle through the complicated world of MFF ubiquitination together! Thank you to the Wellcome Trust for funding me and for giving me the opportunity to carry out this programme of research, and to my course mates, Dani and Jenny, for going through this together and always being up for a pint! To Sofia, thank you for your encouragement, support and making me believe I can do anything. Also, for reminding me to take it easy from time to time (and all the amazing food and coffee!). You have made this journey so enjoyable, through the highs and lows, and you always put a smile on my face. And, of course, thank you to my family for your support. My deepest thanks go to my parents, I would not be where I am if it wasn’t for your continued belief in me. I am truly grateful for your love and encouragement in all my endeavours. iii Abbreviations AD Alzheimer’s Disease ADP Adenosine Diphosphate AMP Adenosine Monophosphate AMPK AMP-activated protein kinase ATP Adenosine Triphosphate BRAC Breast Cancer Type 1 Susceptibility Protein BSA Bovine Serum Albumin CCCP carbonyl cyanide m-chlorophenylhydrazone CENP-E Centromere protein-E DIV Days in vitro DRP1 Dynamin Related Protein 1 Dyn2 Dynamin-2 Elk-1 ETS domain transcription factor ER Endoplasmic Reticulum ERMES ER-Mitochondrial Encounter Structure ETC Electron Transport Chain FBS Foetal Bovine serum Fis1 Mitochondrial Fission protein 1 GTP Guanosine Triphosphate HDAC Histone Deacetylase HEK Human Embryonic Kidney HIF-1α Hypoxia-inducible factor 1-alpha HSF Heat Shock factor IκBα NF-kappa-B inhibitor alpha IP Immunoprecipitation IMM Inner Mitochondrial Membrane MAPK Mitogen Activated protein Kinase iv MARCH5 Membrane Associated RING-finger 5 MAPL Mitochondrial Anchored Protein Ligase MR Mitochondrial Reticulum MFF Mitochondrial Fission Factor MEF Mouse Embryonic Fibroblast MEF2A Myocyte-specific enhancer factor 2A MiD Mitochondrial Dynamics proteins MOM Mitochondrial Outer Membrane NB Nuclear Body NEM N-Ethylmaleimide NF-κB Nuclear Factor Kappa-light-chain-enhancer of activated B cells OGD Oxygen Glucose Deprivation OXPHOS Oxidative Phosphorylation PD Parkinson’s Disease PDL Poly D-Lysine PDSM Phosphorylation Dependent SUMO consensus motif PGC-1α Peroxisome proliferator-activated receptor gamma coactivator 1-α PINK1 PTEN Induced Kinase-1 PKA Protein Kinase A PKC Protein Kinase C PLL Poly L-Lysine PML Promyelocytic Leukaemia Protein PTM Post Translational Modification Ran-Gap RAS-related Nuclear GTPase activating Protein RCF Relative Centrifugal Force RING Really Interesting New Gene RNF4 RING Finger Protein 4 SAE SUMO Activating Enzyme SDM Site Directed Mutagenesis v SDS Sodium Dodecyl Sulphate SDS-PAGE Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis SENP Sentrin/SUMO-specific proteases SIM SUMO Interacting Motif SIMH Stress Induced Mitochondrial Hyperfusion STAT signal transducer and activator of transcription STUbL SUMO targeted Ubiquitin Ligase SUMO Small Ubiquitin like Modifier TF Transcription Factor TCA Tricarboxylic acid cycle Ubl Ubiquitin Ligase ULK1 Unc-51-Like Kinase 1 USP Ubiquitin Specific Protease WT Wildtype vi List of Figures Figure 1.1 The SUMO cycle .............................................................................. 10 Figure 1.2 Phosphorylation-dependent SUMOylation ....................................... 15 Figure 1.3 SUMOylation can initiate multiple downstream effects .................... 21 Figure 1.4 The complex SUMO-ubiquitin “code” ..............................................
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