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Mitochondrial Stress Communication in Mammalian Cells

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Mitochondrial Stress Communication in Mammalian Cells MITOCHONDRIAL STRESS COMMUNICATION IN MAMMALIAN CELLS Jayne Barbour A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy School of Medical Sciences, Faculty of Medicine 2017 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Barbour First name: Jayne Other name/s: Alexandra Abbreviation for degree as given in the University calendar: PhD School: Medical Sciences Faculty: Medicine Title: Mitochondrial Stress Communication in Mammalian Cells Abstract 350 words maximum: (PLEASE TYPE) Mitochondria are crucial organelles in energy transduction, with an emerging role in cell signaling beginning to be appreciated. Due to the endosymbiotic nature of mitochondria and as a by-product of energy transduction via the electron transport chain (ETC), mitochondria are inherently exposed to many stresses (e.g. reactive oxygen species, genomic damage and proteotoxic stress). We postulated that there would be active intracellular and extracellular pathways of mitochondrial communication engaged to maintain cellular fitness, however this has not been well studied in mammalian cells. The overarching aim of this thesis was to explore how mammalian cells communicate mitochondrial stress. More specifically, to characterise intracellular signaling adaptations to mitochondrial stress and to investigate cell non- autonomous communication of mitochondrial stress through secreted proteins. To address the first aim, a xeno-cybrid model was employed where cells had mismatch between nuclear and mitochondrial genomes resulting in an impairment of ETC function. Compared with controls, cells with ETC dysfunction had substantial oxidative defects, but were viable and maintained cellular ATP. This ‘rescue’ of cell survival appeared to be driven by upregulation of glycolysis and pro-survival Akt and AMPK signaling. To interrogate a potential upstream mediator, ATM kinase was explored, and it was found that a number of adaptations were reversed by a selective ATM kinase inhibitor. These results therefore support a role for ATM kinase as an important adaptation promoting survival of mammalian cells in response to mitochondrial stress. To address cell non-autonomous communication, HEK293 cells, and primary murine hepatocytes and adipocytes were incubated with ETC inhibitors (rotenone or antimycin A) or an oxidative phosphorylation uncoupler (Dinitrophenol), and secreted proteins were analysed by LC-MS/MS to map the mitochondrial stress-sensitive secretome. Significant alterations in secreted proteins were observed for HEK293 cells and adipocytes with ETC complex I and III inhibition and in hepatocytes treated with DNP. Collectively, the work presented in this thesis sheds new light on the pathways employed by mammalian mitochondria to signal and respond to stress. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… Date Signature Witness Signature The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed ……………………………………………...... Date … ………………………………………….............. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……………………………………………........................... TABLE OF CONTENTS THESIS ABSTRACT .................................................................................................................................... i ACKNOWLEDGEMENTS .......................................................................................................................... ii LIST OF FIGURES ..................................................................................................................................... iv LIST OF TABLES ...................................................................................................................................... vii CHAPTER 1: INTRODUCTION .................................................................................................................. 1 1.1 Mitochondria: From Origins to Function ............................................................................................. 1 1.1.1 The Endosymbiotic Origins of Mitochondria ............................................................................... 1 1.1.2 Mitochondrial Structure and Dynamics ........................................................................................ 2 1.1.3 The Mitochondrial Genome .......................................................................................................... 6 1.1.4 Mitochondrial Biogenesis .............................................................................................................. 8 1.1.5 Mitochondrial Oxidative Phosphorylation .................................................................................. 12 1.1.6 Mitochondria and Apoptosis ....................................................................................................... 14 1.2 Mitochondria are Inherently Stressful Organelles ............................................................................. 15 1.2.1 Oxidative Stress ........................................................................................................................... 15 1.2.2 Genomic Stress ............................................................................................................................ 17 1.2.3 Proteotoxic Stress ........................................................................................................................ 19 1.2.4 Mitochondrial Vulnerability to Exogenous Stress ...................................................................... 20 1.3 Mitochondrial Stress Communication and Quality Control is required for Maintenance of Symbiotic Relationship between Mitochondria and the Cell .................................................................................... 22 1.3.1 Anterograde Communication ...................................................................................................... 22 1.3.2 Retrograde Communication ..................................................................................................... 24 1.4 Mitochondria and Disease: A Role for Mitochondrial Stress and Communication? ......................... 40 1.4.1 Mitochondrial Disease ................................................................................................................. 40 1.4.2 Mitochondrial Function and Communication in the Aetiology
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