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Strategies for Preventing Age and Neurodegenerative Disease-Associated Mitochondrial Dysfunction Vedad Delic University of South Florida, [email protected]

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Strategies for Preventing Age and Neurodegenerative Disease-Associated Mitochondrial Dysfunction Vedad Delic University of South Florida, Delic2@Mail.Usf.Edu University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School January 2015 Strategies for Preventing Age and Neurodegenerative Disease-associated Mitochondrial Dysfunction Vedad Delic University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Cell Biology Commons, Molecular Biology Commons, and the Neurosciences Commons Scholar Commons Citation Delic, Vedad, "Strategies for Preventing Age and Neurodegenerative Disease-associated Mitochondrial Dysfunction" (2015). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/5676 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Strategies for Preventing Age and Neurodegenerative Disease-associated Mitochondrial Dysfunction by Vedad Delic A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy with a concentration in Cell and Molecular Biology Department of Cell Biology, Microbiology, and Molecular Biology College of Arts and Sciences University of South Florida Major Professor Patrick Bradshaw, Ph.D. Paula Bickford, Ph.D. Bruce Citron, Ph.D. Kristina Schmidt, Ph.D. Stanley Stevens, Ph.D. Date of Approval: April, 21, 2015 Keywords: ALS, melatonin, tau, amyloid-beta, metabolic intermediates Copyright © 2015, Vedad Delic DEDICATION I dedicate this work to my siblings Hana and Haris Delic who continue to be the source of inspiration for every experiment I do. I also dedicate this work to U.S. Army Staff Sergeant (retired) Charles Claybaker for his unwavering support for neurodegenerative research and for his service to this country. ACKNOWLEDGMENTS I would like to acknowledge members of the Bradshaw lab for their help with experiments over the years: Stephen Bell, Crupa Curien, Charles Claybaker, Eni Cvitkovic, Josean Cruz, Vinh Dinh, Ernide Frederic, Mira Janjus, Stacy Medrano, Emily Nickoloff, Kenyaria Noble, Tam-Anh Phan, Oluwakemi Philips, Christian Reynes, and Yumeng Zhang. I would also like to acknowledge the University of South Florida Department of Cell Biology, Microbiology, and Molecular Biology for an amazing education and the opportunity to pursue my Ph.D. I would like to acknowledge my parents Erna and Hamdija “Bruce” Delic for emotional and financial support during graduate school as well as Avi, Edin, and Mike for being understanding friends. Lastly, I would like to acknowledge exceptional faculty for the incredible opportunities they have provided me both as mentors and as collaborators: Dr. Patrick Bradshaw, Dr. Bruce Citron, Dr. Svitlana Garbuzova-Davis, Dr. Richard Pollenz, and Dr. K.T. Scott. TABLE OF CONTENTS LIST OF TABLES ........................................................................................................................ vii LIST OF FIGURES ..................................................................................................................... viii ABBREVIATIONS ....................................................................................................................... ix ABSTRACT ................................................................................................................................... xi CHAPTER ONE: INTRODUCTION ............................................................................................. 1 Mitochondrial electron transport chain and oxidative phosphorylation ............................. 2 Mitochondrial fusion and fission ........................................................................................ 6 Cell signaling, activation of a stress response, and iron metabolism.................................. 7 Mitochondrial cell signaling ................................................................................... 7 Mitochondrial stress response ................................................................................. 9 Iron metabolism .................................................................................................... 11 Roles of mitochondria in aging and neurodegenerative diseases ..................................... 12 Aging and mitochondria ....................................................................................... 13 Alzheimer’s and mitochondria .............................................................................. 14 Parkinson’s disease and mitochondria .................................................................. 16 ALS and mitochondria .......................................................................................... 18 Descriptive statistical analysis .......................................................................................... 22 Outcomes of the following studies ................................................................................... 22 CHAPTER TWO: CALORIE RESTRICTION DOES NOT RESTORE BRAIN MITOCHONDRIAL FUNCTION IN P301L TAU MICE, BUT IT DOES DECREASE MITOCHONDRIAL fOf1-atpase ACTIVITY ................................................................................................................. 23 Abstract ............................................................................................................................. 23 Introduction ....................................................................................................................... 24 Material and methods ........................................................................................................ 26 Mice and experimental design .............................................................................. 26 Mitochondrial isolation ......................................................................................... 28 Oxygen consumption analysis .............................................................................. 28 Reactive oxygen species level measurements ....................................................... 29 Mitochondrial membrane potential determination ................................................ 29 ATP synthesis assays in isolated mitochondria .................................................... 30 F0F1-ATPase activity measurements..................................................................... 30 ATP synthesis assays in permeabilized N2a and HEK293 cells .......................... 31 Western blots ........................................................................................................ 32 Protein assays ........................................................................................................ 33 i Statistical analysis ................................................................................................. 33 Results ............................................................................................................................... 33 Mitochondria from Tg4510 mice show decreased state 3 oxygen consumption rates and respiratory control ratios ............................... 33 Mitochondria from Tg4510 mice show increased ROS production in the presence of ethanol stress...................................................................... 34 Mitochondria from Tg4510 mice show increased membrane potential ............... 35 CR does not restore the reduced mitochondrial ETC complex I activity in Tg4510 mitochondria ..................................................................... 35 No change in the levels of the alpha and beta subunits of ATP synthase in isolated mitochondria from Tg4510 mice ........................... 36 No change in isolated mitochondrial ATP production in Tg4510 mice or in CR mice ............................................................................ 36 A decreased rate of mitochondrial ATP synthesis in digitonin-permeabilized N2a-P301L tau cells ................................................ 37 Mitochondria from CR mice show decreased F0F1-ATPase activity .................... 38 Discussion ......................................................................................................................... 38 Tau inhibition of mitochondrial ETC complex I .................................................. 38 Tau expression does not decrease F0F1-ATPase activity or the levels of two ATP synthase subunits ........................................................ 39 Behavior of Tg4510 mice on the CR diet ............................................................. 39 Possible mechanisms for the decreased state 3, but not state 5 respiration rate in mitochondria from Tg4510 mice ............................ 40 Possible mechanisms through which CR decreases F0F1-ATPase activity .......... 42 Conclusions ....................................................................................................................... 43 Acknowledgments............................................................................................................. 44 CHAPTER THREE: MELATONIN’S MITOCHONDRIAL PROTECTIVE ROLE IN ALZHEIMER’S MICE: ROLE OF MELATONIN RECEPTORS ...................................................................................................... 54 Abstract ............................................................................................................................. 54 Alzheimer’s Disease ........................................................................................................
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