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Mark Adam Scott Mitochondrial Survival Without Oxygen

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Mark Adam Scott Mitochondrial Survival Without Oxygen Mark Adam Scott Mitochondrial survival without oxygen Faculty of Mathematics and Natural Sciences University of Oslo 2017 Mitochondrial survival without oxygen By Mark Adam Scott Thesis presented for the degree of PHILOSOPHIAE DOCTOR Department of Biosciences Faculty of Mathematics and Natural Sciences University of Oslo 2017 © Mark Adam Scott, 2018 Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo No. 1949 ISSN 1501-7710 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. Acknowledgements I would like to begin by expressing my gratitude to Göran Nilsson, Kåre-Olav Stensløkken, the Research Council of Norway, the European Research Council, and the University of Oslo for creating this opportunity for me. I am fortunate to have had supervisors that allowed me the freedom to explore the techniques that I was interested in developing. I am also grateful that my PhD enabled me not just to achieve the academic goals that I had set for myself but several other goals as well. Chief among them, being able to see as much of Europe as I’d hoped to. I was fortunate to have a talented and supportive group of colleagues and office mates throughout my PhD. Thank you Sjannie, Christina, Marco, Anette, and especially Cathrine, thank you for teaching me everything I needed to know about the entire process of qPCR, from cloning through to analysis. Antje, thank you for welcoming me into the world of electron microscopy. Steinar, thank you for solving many of the logistical issues I had over the years. Haaken, thank you for saving me countless hours of animal husbandry. I arrived in Norway to start my PhD without knowing anyone and I would like to express my appreciation to a few wonderful people I met over the years. Thank you Jon for taking me along on all the cabin trips and introducing me to your friends. It meant a lot to me. Ivan, it has been a privilege. Nacho, it’s a shame we didn’t meet sooner. Knut, thanks for the adventures. Siri & May-Kristin, you brightened every day. Andreas, still 4.9%. Danny, sorry for Cards Against Humanity. Lench, thanks for the Shepherd’s pie. And a heartfelt thank you to my Italian sis, I would not have managed it without your support. Lastly, I would like to acknowledge my family and friends for their support throughout the writing process. I appreciated every home-cooked meal and the distractions of pub quizzes, beer pong, Catan, and a whole lot of pho. Table of Contents Abstract ------------------------------------------------------------------------------------------------------------------- 1 List of papers -------------------------------------------------------------------------------------------------------------- 5 Abbreviations ------------------------------------------------------------------------------------------------------------- 6 Introduction --------------------------------------------------------------------------------------------------------------- 8 General introduction ------------------------------------------------------------------------------------------------ 8 Model organisms ----------------------------------------------------------------------------------------------------- 9 Mitochondria --------------------------------------------------------------------------------------------------------10 Membrane potential ------------------------------------------------------------------------------------------12 Ultrastructure ---------------------------------------------------------------------------------------------------13 Metabolomics ---------------------------------------------------------------------------------------------------15 Anoxia -----------------------------------------------------------------------------------------------------------------18 Membrane potential ------------------------------------------------------------------------------------------19 Ultrastructure ---------------------------------------------------------------------------------------------------21 Metabolomics ---------------------------------------------------------------------------------------------------23 Concluding paragraph ---------------------------------------------------------------------------------------------26 Aims -----------------------------------------------------------------------------------------------------------------------28 Methods ------------------------------------------------------------------------------------------------------------------30 Animals ---------------------------------------------------------------------------------------------------------------30 Isolation of ventricular myocytes ------------------------------------------------------------------------------30 Fixed cell IA experiments -----------------------------------------------------------------------------------------31 Live-cell TMRM experiments ------------------------------------------------------------------------------------31 Fluorescence Microscopy ----------------------------------------------------------------------------------------32 Anoxia exposure and tissue sampling -------------------------------------------------------------------------32 Enzyme activities ---------------------------------------------------------------------------------------------------33 Electron microscopy -----------------------------------------------------------------------------------------------33 Obtaining sequences for ATP synthase -----------------------------------------------------------------------35 qPCR -------------------------------------------------------------------------------------------------------------------36 Metabolomics -------------------------------------------------------------------------------------------------------38 Summary of Results ---------------------------------------------------------------------------------------------------40 Paper I -----------------------------------------------------------------------------------------------------------------40 Paper II ----------------------------------------------------------------------------------------------------------------43 Paper III ---------------------------------------------------------------------------------------------------------------45 General Discussion ----------------------------------------------------------------------------------------------------47 Maintenance of mitochondrial membrane potential -----------------------------------------------------47 Reducing ATP demand and increasing ATP supply in anoxia --------------------------------------------50 Mitochondrial fusion and ultrastructure ---------------------------------------------------------------------53 Conclusion -----------------------------------------------------------------------------------------------------------56 i Literature Cited ---------------------------------------------------------------------------------------------------------57 Papers I-III ii Abstract Heart research is increasingly important from both a basic and medical physiology stand point. The heart is an energetically demanding tissue and heart disease accounts for a high proportion of human disease- related mortality. Blood vessels can become clogged, oxygen and nutrients diverted, and suddenly the cells of the heart are unable to meet the energetic requirements necessary to function. Under normal conditions mitochondria are the main site of cellular energy supply, but during oxygen deprivation they switch to being a major site for cellular energy consumption. A comprehensive understanding of basic mitochondrial pathophysiology is a crucial component of addressing the current heart disease pandemic. Once deprived of oxygen, the human heart can only function for minutes before a person succumbs to the trauma. The crucian carp, however, can maintain normal cardiac function in anoxia for days to months depending on the temperature. Research into the adaptations of the crucian carp heart is limited and investigations into crucian carp heart mitochondria have been nonexistent. It was not known how the crucian carp heart mitochondria maintained energy supply without oxidative phosphorylation nor how the mitochondria averted lethal energy consumption as is observed within minutes in humans. The following experiments were undertaken to address these two critical components of mitochondrial pathophysiology. The experiments presented in Paper I investigate how mitochondrial membrane potential (ΔΨM) is affected by blockers of the electron transport chain (ETC). The maintenance of ΔΨM is essential to cellular survival and a loss of ΔΨM characterises an irreversible cascade towards cell death. It was not known what happens to crucian carp ΔΨM following exposure to simulated anoxia. Isolated cardiomyocytes from the anoxia-tolerant crucian carp and anoxia-intolerant brown trout were loaded with the mitochondrial fluorescent stain tetramethylrhodamine methyl ester perchlorate (TMRM) and exposed to rotenone, antimycin, cyanide, and oligomycin. Crucian carp cardiomyocytes were found to maintain ΔΨM for much longer than trout when Complex IV of the ETC was blocked with cyanide (simulating anoxia). Additionally, inhibition of Complex V (ATP synthase) accelerated the loss of ΔΨM, + suggesting that this enzyme is acting in reverse, as an ATP consuming H pump to preserve ΔΨM
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