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Stony Brook University SSStttooonnnyyy BBBrrrooooookkk UUUnnniiivvveeerrrsssiiitttyyy The official electronic file of this thesis or dissertation is maintained by the University Libraries on behalf of The Graduate School at Stony Brook University. ©©© AAAllllll RRRiiiggghhhtttsss RRReeessseeerrrvvveeeddd bbbyyy AAAuuuttthhhooorrr... Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function A Dissertation Presented by Jae Kyo Yi to The Graduate School in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Molecular and Cellular Biology Stony Brook University August 2016 Stony Brook University The Graduate School Jae Kyo Yi We, the dissertation committee for the above candidate for the Doctor of Philosophy degree, hereby recommend acceptance of this dissertation. Cungui Mao, Ph.D. - Dissertation Advisor Associate Professor, School of Medicine Bruce Demple, Ph.D. - Chairperson of Defense Professor, Department of Pharmacological Sciences Yusuf Hannun, M.D. Director of Stony Brook Cancer Center, Vice Dean of Cancer Medicine, Joel Strum Kenny Professor in Cancer Research, School of Medicine Lina Obeid, M.D. Dean of Research, Professor of Medicine, School of Medicine Michael Frohman, M.D., Ph.D Director Stony Brook Medical Scientist Training Program, Professor and Chair, Department of Pharmacological Sciences Basil Rigas, M.D., DSc Chief of Division of Cancer Prevention, William and Jane Knapp Professor of Pharmacology, Professor of Medicine, School of Medicine This dissertation is accepted by the Graduate School Nancy Goroff Interim Dean of the Graduate School ii Abstract of the Dissertation Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function by Jae Kyo Yi Doctor of Philosophy in Molecular and Cellular Biology Stony Brook University 2016 Aging is the biological process of growing older in a deleterious sense, senescence. However, what we have gained only comprises a partial and incomplete understanding of the fundamental molecular mechanisms. Increasing evidence suggests that dysregulation of the metabolism of sphingolipids including sphingoid bases (SBs, long-chain bases) might play an important role in the aging. We know neither how SBs are regulated during yeast aging nor how they, in turn, regulate it. Herein, I demonstrate that the yeast alkaline ceramidases (YPC1 and YDC1) and SB kinases (LCB4 and LCB5) cooperate in regulating SBs during the aging process and that SBs shorten chronological life span (CLS) by compromising mitochondrial functions. With a lipidomics approach, I found that SBs were increased in a time-dependent manner during yeast aging. I also demonstrated that among the enzymes known for being responsible for the metabolism of SBs, YPC1 was upregulated whereas LCB4/5 were downregulated in the course of iii aging. This inverse regulation of YPC1 and LCB4/5 led to not only the aging-related upregulation of SBs in yeast but also a reduction in CLS. With the proteomics-based approach (SILAC), I revealed that increased SBs altered the levels of proteins related to mitochondria. Further mechanistic studies demonstrated that increased SBs inhibited mitochondrial fusion and caused fragmentation, resulting in decreases in mtDNA copy numbers, ATP levels, mitochondrial membrane potentials, and oxygen consumption. As the metabolism of sphingolipids is highly conserved between yeast and mammalian cells, these important findings would also facilitate our understanding of the role and mechanism of the action of sphingolipids and their metabolizing enzymes in physiological and pathological aging of humans and other mammals. iv Dedication page I would like to dedicate my thesis to my beloved parents who always encourage me to pursue my dream and to go on every adventure, especially this one. v Table of Contents Chapter 1. Background and Significance ................................................................................... 1 1.1 Aging ................................................................................................................................ 1 1.1.1 Introduction of aging .............................................................................................. 1 1.1.2 Roles of mitochondria in aging .............................................................................. 2 1.1.3 The oxidative stress and aging ............................................................................... 4 1.2 Sphingolipids .................................................................................................................. 6 1.2.1 Sphingolipid metabolism ........................................................................................ 6 1.2.1.1 Sphingolipid metabolism in human ................................................................... 6 1.2.1.2 Sphingolipid metabolism in yeast ...................................................................... 8 1.2.2 Sphingolipid structure ............................................................................................ 9 1.3 Roles of sphingolipids in biological processes ............................................................ 10 1.3.1 Roles of sphingolipids in differentiation ............................................................. 10 1.3.2 Roles of sphingolipids in programmed cell death .............................................. 11 1.3.3 Roles of sphingolipids in cell adhesion and migration ....................................... 13 1.3.4 Roles of sphingolipids in angiogenesis ................................................................ 14 1.3.5 Roles of sphingolipids in inflammation ............................................................... 15 1.3.6 Roles of sphingolipids in cellular senescence and aging .................................... 16 1.3.7 Roles of sphingolipids in aging-related diseases ................................................. 20 1.3.8 Roles of sphingolipids in signal transduction ..................................................... 22 vi 1.4 Figures and tables......................................................................................................... 24 Chapter 2. Sphingoid bases are accumulated in yeast cells during the aging process. ........ 28 2.1 Introduction .................................................................................................................. 28 2.2 Results ........................................................................................................................... 28 2.2.1 Sphingoid bases and their metabolizing enzymes are regulated in yeast cells during aging process ............................................................................................................ 28 2.2.2 Inverse regulation of alkaline ceramidases and sphingoid base kinases leads to aging-induced elevation of sphingoid bases in yeast cells ................................................ 30 2.2.3 MSN2/4 are required for YPC1 regulation during aging ................................. 31 2.3 Discussion ...................................................................................................................... 32 2.4 Materials and Methods ................................................................................................ 35 2.4.1 Yeast strains, media and growth conditions ....................................................... 35 2.4.2 Sphingolipid analyses ........................................................................................... 36 2.4.3 Quantitative mRNA levels of sphingolipid metabolism enzymes ..................... 36 2.4.4 Ceramidase activity assay .................................................................................... 37 2.5 Figures and tables............................................................................................................ 37 Chapter 3. Accumulation of sphingoid bases leads to yeast aging ......................................... 47 3.1 Introduction .................................................................................................................. 47 vii 3.2 Results ........................................................................................................................... 47 3.2.1 Upregulation of sphingoid bases reduces yeast chronological life span .......... 47 3.3 Discussion ...................................................................................................................... 49 3.4 Materials and Methods ................................................................................................ 50 3.4.1 CLS assays ................................................................................................................... 50 3.4.2 Protein expression analysis ........................................................................................ 50 3.4.3 Statistical analysis ....................................................................................................... 50 3.5 Figures and tables.............................................................................................................. 52 Chapter 4. Accumulation of sphingoid bases disrupts mitochondrial structure and function ....................................................................................................................................................... 54 4.1 Introduction .................................................................................................................
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