biology Mitochondrial Dysfunction in Aging and Diseases of Aging Edited by Richard H. Haas Printed Edition of the Special Issue Published in Biology www.mdpi.com/journal/biology Mitochondrial Dysfunction in Aging and Diseases of Aging Mitochondrial Dysfunction in Aging and Diseases of Aging Special Issue Editor Richard H. Haas MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Richard H. Haas UC San Diego School of Medicine USA Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Biology (ISSN 2079-7737) in 2019 (available at: https://www.mdpi.com/journal/biology/special issues/ Mitochondria) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03921-327-6 (Pbk) ISBN 978-3-03921-328-3 (PDF) Cover image courtesy of Scott McAvoy. c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editor ...................................... vii Preface to ”Mitochondrial Dysfunction in Aging and Diseases of Aging” ............ ix Richard H. Haas Mitochondrial Dysfunction in Aging and Diseases of Aging Reprinted from: Biology 2019, 8, 48, doi:10.3390/biology8020048 ................... 1 Peter J. McGuire Mitochondrial Dysfunction and the Aging Immune System Reprinted from: Biology 2019, 8, 26, doi:10.3390/biology8020026 ................... 6 Robert K. Naviaux Incomplete Healing as a Cause of Aging: The Role of Mitochondria and the Cell Danger Response Reprinted from: Biology 2019, 8, 27, doi:10.3390/biology8020027 ................... 16 Isabella Peixoto de Barcelos and Richard H. Haas CoQ10 and Aging Reprinted from: Biology 2019, 8, 28, doi:10.3390/biology8020028 ................... 34 Roisin Stout and Mark Birch-Machin Mitochondria’s Role in Skin Ageing Reprinted from: Biology 2019, 8, 29, doi:10.3390/biology8020029 ................... 56 Sunil J. Wimalawansa Vitamin D Deficiency: Effects on Oxidative Stress, Epigenetics, Gene Regulation, and Aging Reprinted from: Biology 2019, 8, 30, doi:10.3390/biology8020030 ................... 68 Janis T. Eells Mitochondrial Dysfunction in the Aging Retina Reprinted from: Biology 2019, 8, 31, doi:10.3390/biology8020031 ................... 83 Yvonne Will, Jefry E. Shields and Kendall B. Wallace Drug-Induced Mitochondrial Toxicity in the Geriatric Population: Challenges and Future Directions Reprinted from: Biology 2019, 8, 32, doi:10.3390/biology8020032 ................... 92 Magdalene K Montgomery Mitochondrial Dysfunction and Diabetes: Is Mitochondrial Transfer a Friend or Foe? Reprinted from: Biology 2019, 8, 33, doi:10.3390/biology8020033 ...................106 Jason Duran, Armando Martinez and Eric Adler Cardiovascular Manifestations of Mitochondrial Disease Reprinted from: Biology 2019, 8, 34, doi:10.3390/biology8020034 ...................123 Nima B. Fakouri, Thomas Lau Hansen, Claus Desler, Sharath Anugula and Lene Juel Rasmussen From Powerhouse to Perpetrator—Mitochondria in Health and Disease Reprinted from: Biology 2019, 8, 35, doi:10.3390/biology8020035 ...................150 v Veronica Granatiero and Giovanni Manfredi Mitochondrial Transport and Turnover in the Pathogenesis of Amyotrophic Lateral Sclerosis Reprinted from: Biology 2019, 8, 36, doi:10.3390/biology8020036 ...................165 Isabella Peixoto de Barcelos, Regina M. Troxell and Jennifer S. Graves Mitochondrial Dysfunction and Multiple Sclerosis Reprinted from: Biology 2019, 8, 37, doi:10.3390/biology8020037 ...................179 Chun Chen, Doug M. Turnbull and Amy K. Reeve Mitochondrial Dysfunction in Parkinson’s Disease—Cause or Consequence? Reprinted from: Biology 2019, 8, 38, doi:10.3390/biology8020038 ...................195 Ian Weidling and Russell H. Swerdlow Mitochondrial Dysfunction and Stress Responses in Alzheimer’s Disease Reprinted from: Biology 2019, 8, 39, doi:10.3390/biology8020039 ...................221 Mats I Nilsson and Mark A Tarnopolsky Mitochondria and Aging—The Role of Exercise as a Countermeasure Reprinted from: Biology 2019, 8, 40, doi:10.3390/biology8020040 ...................239 vi About the Special Issue Editor Richard Haas M.A., M.B., B.Chir., M.R.C.P. is a Professor of Neurosciences and Pediatrics at the University of California San Diego. He is Director of the Neurometabolic Clinics at Rady Children’s Hospital San Diego and the UCSD Adult Neurometabolic Clinic. He directs the UCSD Mitochondrial Disease Laboratory and is Co-director of the UCSD Mitochondrial and Metabolic Disease Center. He directs the fellowship training program of the North American Mitochondrial Disease Consortium. Dr. Haas received his undergraduate training at Cambridge University and studied clinical medicine at University College Hospital in London, Great Ormond Street Hospital and the Royal Postgraduate Medical School Hammersmith. He trained in metabolism and pediatric neurology as NIH Fellow in Biochemistry of Mental Retardation at the University of Colorado, Denver. His clinical and research focus for 40 years has been on mitochondrial disease and in 1998 he was Founding President of the Mitochondrial Medicine Society. In 2016 he was awarded the Vanguard award by the United Mitochondrial Disease Foundation and he serves on the Scientific and Medical Advisory Board. vii Preface to ”Mitochondrial Dysfunction in Aging and Diseases of Aging” Mitochondria are increasingly recognized as important players in the aging process. Most aging-related diseases, particularly neurodegenerative diseases, involve the mitochondria. A PubMed search for mitochondria and aging produced 348 articles from the first seven months of 2018. This is not surprising considering that mitochondria are not only involved in energy production through oxidative phosphorylation, but also play an important role in intracellular homeostasis, calcium balance, and the metabolism and interconversion of dietary substrates—fats, proteins, and carbohydrates in the fed and fasting states. They signal their metabolic state to the nucleus, to other cells and in response to stress. Mitochondria have their own protein synthetic apparatus and are able to replicate the pathways readily disrupted in disease and aging. They are constantly involved in fusion and fission, the balance of which is essential for cell health. These organelles participate in apoptosis, make most of the cell’s free radicals, and are crucial for innate immunity. Mitochondrial DNA has an estimated 10-fold greater mutation rate than nuclear DNA, and less repair capacity, important factors in aging and cancer. Mitochondria are impacted by environmental factors and toxins, and different mtDNA haplogroups that originally adapted to different geographic origins are important contributors to disease. As mitochondria play a critical metabolic role in all organ systems, they are particularly impacted by disease and contribute to the aging process itself. The invited review articles in this supplement cover most of the common diseases of aging. This edition of Biology aims to review the current state of knowledge about the role of mitochondria in the aging process. The international group of contributing authors includes many leading experts in their fields. Richard H. Haas Special Issue Editor ix biology Editorial Mitochondrial Dysfunction in Aging and Diseases of Aging Richard H. Haas 1,2 1 Department of Neurosciences, University of California San Diego, San Diego, CA 92093-0935, USA; [email protected] 2 Department of Pediatrics, University of California San Diego, San Diego, CA 92093-0935, USA Received: 10 June 2019; Accepted: 11 June 2019; Published: 17 June 2019 Mitochondria have been increasingly recognized as the important players in the aging process. Most aging-related diseases, particularly, neurodegenerative diseases, have mitochondrial involvement. A PubMed search for mitochondria and aging lists 704 articles in 2018. This is not surprising as mitochondria are involved not only in energy production through oxidative phosphorylation but also play an important role in intracellular homeostasis, calcium balance, and the metabolism and interconversion of our dietary substrates, fats, proteins, and carbohydrates, in the fed and fasting states. They have an important role in signaling their metabolic state to the nucleus and to other cells in response to stress. Mitochondria have their own protein synthetic apparatus and replicate themselves, pathways readily disrupted in disease and aging. They are constantly involved in fusion and fission, the balance of which is essential for cell health. These organelles participate in apoptosis, they make most of the cell’s free radicals, and they are crucially important for innate immunity. Mitochondrial DNA has an estimated 10-fold greater mutation rate than nuclear DNA and less repair capacity, and this plays an important role in aging and cancer. Mitochondria are impacted by environmental factors and toxins, and different mtDNA