title: Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function.
abstract: Sphingoid bases (SBs) as bioactive sphingolipids, have been implicated in aging in yeast. However, we know neither how SBs are regulated during yeast aging nor how they, in turn, regulate it. Herein, we 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 shortens chronological life span (CLS) by compromising mitochondrial functions. With a lipidomics approach, we found that SBs were increased in a time-dependent manner during yeast aging. We 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 aging. This inverse regulation of YPC1 and LCB4/5 led to the aging-related upregulation of SBs in yeast and a reduction in CLS. With the proteomics-based approach (SILAC), we 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. Taken together, these results suggest that increased SBs mediate the aging process by impairing mitochondrial structural integrity and functions.
authors.affiliation: Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY, USA.|Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Jae Kyo
authors.initials: JK
authors.lastname: Yi
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Eunmi
authors.initials: E
authors.lastname: Jeong
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Izolda
authors.initials: I
authors.lastname: Mileva
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Truman
authors.affiliation: Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY, USA.|Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY, USA.|Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Snider
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.|Northport Veterans Affairs Medical Center, Northport, NY, USA.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook, NY, USA.
authors.forename: Cungui
authors.initials: C
authors.lastname: Mao
mesh_terms: D000375:Aging / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D002518:Ceramides; D004272:DNA, Mitochondrial; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids
keywords: Gerotarget; aging; mitochondria; sphingoid bases; sphingolipids; yeast