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Mitochondrial Calcium Uptake Pathways As a Potential Therapeutic Target

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Mitochondrial Calcium Uptake Pathways As a Potential Therapeutic Target Mitochondrial calcium uptake pathways as a potential therapeutic target. Julia Marie Hill A thesis submitted for the degree of Doctor of Philosophy Department of Cell and Developmental Biology University College London January 2016 I dedicate this thesis to Neil and Jill Hill, who have always encouraged me to strive, and have always had confidence in me. 2 Declaration I, Julia Marie Hill, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. January, 2016 Julia Marie Hill 3 Acknowledgements I would like to thank Professor Michael Duchen and Professor Gyorgy Szabadkai for their supervision and guidance throughout my studies and research. Thank you especially to Gyuri for his extensive practical as well as theoretical knowledge, for doing experiments alongside me when necessary, and encouraging me when I was disheartened. I would also like to thank Eisai for funding my PhD. Without funding I would certainly not have been able to undertake a PhD. A big thank you is owed to all members of the Duchen and Szabadkai labs, past and present. Drs Zhi Yao, Will Kotiadis, Goncalo Pereira, Nicoletta Plotegher, Tom Briston, Laura Osellame and Jose Vicencio for teaching me many of the techniques I have used in the lab, in addition to their good advice and friendship. Thanks especially to Zhi, Will and Goncalo for your enduring patience and assistance. Many, many thanks also go to Bobby Bentham, Stephanie Sundier, Jenny Sharpe, Gauri Bhosale, Pedro Guedes Dias, Greg Keen and Neta Amior for making my time here not only bearable but enjoyable, it wouldn’t have been anywhere near as fun without you. Thank you to Sam Ranasinghe, for keeping the confocals working, and coming to the rescue whenever they weren’t. I extend my thanks also to Dr Gareth Pryce and Professor David Baker of the Blizard Institute at Queen Mary’s, and to Professor David Selwood of the Wolfson Institute for Biomedical Research for their collaboration, and for putting me in touch with their fascinating research. Thanks especially to Gareth for all those days spent together mashing up livers, and for not giving up when it wasn’t working. Thank you also to Dr Sean Davidson and Dr Dan Bromage for supplying me with CypD-/- mice from their colony at no cost and no inconvenience. I would also like to express my gratitude to UCL’s Biological Services and Biosciences Stores for their underappreciated hard work and consistent cheerfulness. On a personal note, I want to thank my friends and family who have supported me throughout the PhD. These are too numerous to name, but special thanks go to Ernestas Sirka, my fabulous flatmate of the last three years, for putting up with me all this time, and being there through it all. 4 Abstract It has been known since the 1960’s that mitochondria have a huge capacity to take up and accumulate calcium from the cytosol, regulating energy production, autophagy, and mitochondrial morphology. Dysfunctional mitochondrial calcium homeostasis is also involved in the pathology of many disease states. Therefore, mitochondrial calcium handling represents an interesting therapeutic target. In this thesis I aimed to investigate related therapeutic avenues and further understand the role of mitochondrial calcium handling machinery. When mitochondrial calcium uptake exceeds the calcium buffering capacity of the mitochondrial matrix, the mitochondrial permeability transition pore (mPTP) opens in the inner mitochondrial membrane. Pore opening causes mitochondrial depolarisation, energetic collapse, swelling, rupture, and cell death. Using isolated mitochondria, I screened a range of novel mitochondrial targeted derivatives of the canonical mPTP inhibitor, cyclosporin A (CsA), to assess their efficacy as mPTP inhibitors, and as potential therapeutics for neurological disease. Two compounds were found to be more effective than CsA at low concentrations, and one was selected for further study. The compound’s target was investigated and found to be Cyclophilin D, and it’s effect on various mitochondrial parameters was assessed, and it was found to be non-toxic ex vivo and in vitro. The molecular identity of the mitochondrial calcium uniporter (MCU) was only recently discovered, followed by discovery of several associated proteins – MCUb, MICU1, MICU2, MICU3, EMRE, and MCUR1. I developed a screen using the bioluminescent protein aequorin to identify mitochondrial specific inhibitors of the MCU, and I developed a stable cell line in which the MCU protein was knocked down, in order to further examine the role of MCU and investigate the effect of reduced mitochondrial calcium uptake on mitochondrial and cellular properties. While mitochondrial calcium uptake was significantly reduced upon stimulation in these cells, cytosolic calcium, oxygen consumption, cell growth and mitochondrial morphology were not affected. I also investigated the protein expression level of the components of the MCU complex in the rat brain throughout development. 5 Publications Some of the figures and ideas presented in this thesis have been published in the following reports: 1. Hill J.M., De Stefani D., Jones A.W., Ruiz A., Rizzuto R., & Szabadkai G., (2014) Measuring baseline Ca2+ levels in subcellular compartments using genetically engineered fluorescent indicators. Methods Enzymol, 543, 47-72. Doi: 10.1016/B978-0-12-801329-8.00003-9. 2. Warne J, Pryce G, Hill JM, Shi X, Lennerås F, Puentes F, et al. Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem 2016; 291(9): 4356-73. 3. Hill J. M., Kriston-Vizi J., Kettler R., Szabadkai G. Developing a screening strategy for mitochondrial specific inhibitors. In preparation. 6 Contents Contents Page Declaration………………………………………………………………………………………………………. 3 Acknowledgements………………………………………………………………………………………….. 4 Abstract……………………………………………………………………………………………………………. 5 Publications……………………………………………………………………………………………………… 6 Contents…………………………………………………………………………………………………………… 7 List of Figures…………………………………………………………………………………………………… 10 List of Tables…………………………………………………………………………………………………….. 13 Abbreviations…………………………………………………………………………………………………… 14 Materials…………………………………………………………………………………………………………. 19 Chapter 1: Introduction……………………………………………..……………………………………. 23 Mitochondria……………………………………………………………………………………………………. 23 Mitochondria and Ca2+ handling………………………………………………………………………. 27 Physiological roles of mitochondrial Ca2+ homeostasis…………………………………. 28 Mitochondrial Ca2+ in apoptosis and necrosis………………………………………………. 30 The Mitochondrial Ca2+ uptake complex…………………………………………………………… 32 MCU…………………………………………………………………………………………………………….. 32 MCUb…………………………………………………………………………………………………………… 36 MICU1…………………………………………………………………………………………………………. 37 MICU2 and MICU3……………………………………………………………………………………….. 40 EMRE…………………………………………………………………………………………………………… 42 MCUR1……………………………………………………………………………………………………….. 43 Solute Carrier 25A23……………………………………………………………………………………. 45 Involvement of other proteins in mitochondrial Ca2+ uptake………………………… 46 The mitochondrial permeability transition pore……………………………………………….. 48 Mechanism of mPTP opening………………………………………………………………………. 48 mPTP and cell fate……………………………………………………………………………………….. 50 Molecular identity of mPTP……………………………………………………………………….... 51 7 Cyclophilin D……………………………………………………………………………………………. 51 A multiprotein complex: VDAC, ANT and TSPO………………………………………... 52 The phosphate carrier……………………………………………………………………………… 53 ATP synthase……………………………………………………………………………………………. 53 Spastic paraplegia 7…………………………………………………………………………………. 56 Mitochondrial Ca2+ as a therapeutic target……………………………………………………….. 57 Roles of mitochondrial Ca2+ overload in neurodegenerative disease……………. 57 Role of mPTP in neurodegenerative disease…………………………………………………. 59 Aims…………………………………………………………………………………………………………………. 61 Chapter 2: Targeting the Mitochondrial Permeability Transition Pore……………. 62 Introduction……………..………………………………………………………………………………………. 62 Existing inhibitors of mPTP…………………………………………………………………………… 62 Methods………………………………………………………………………………………………………….. 67 Results…………………………………………………………………………………………………………….. 73 Initial assessment of compounds…………………………………………………………………. 73 Investigation of JW47 efficacy and target…………………………………………………….. 75 Investigation of the effect of JW47 on mitochondrial parameters……………….. 77 Investigation of second generation compounds…………………………………………… 79 Summary……………………………………………………………………………………………………… 80 Discussion…………………………………………………………………………………………………………. 82 Chapter 3: Developing an Aequorin-based Screening Approach to Identify Inhibitors of MCU ……………………………………………………………………………………………. 89 Introduction……………………………………………………………………………………………………… 89 Mitochondria as drug targets……………………………………………………………………….. 89 Existing MCU-targeting compounds……………………………………………………………… 90 Aequorin………………………………………………………………………………………………………. 91 Designing an aequorin based screening approach………………………………………… 93 Methods…………………………………………………………………………………………………………… 95 Results……………………………………………………………………………………………………………… 100 Initial Screening of the NINDs-2 compound library………………………………………. 100 Reconfirming screening results…………………………………………………………………….. 105 Investigating the effect of compounds on other mitochondrial parameters…. 108 8 Summary……………………………………………………………………………………………………… 110 Discussion…………………………………………………………………………………………………………. 111 Chapter 4: Investigating the role of the MCU in vitro………………………………………. 115 Introduction………………………………………………………………………………………………………
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