Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function

Jae Kyo Yi, Ruijuan Xu, Eunmi Jeong, Izolda Mileva, Jean Philip Truman, Chih li Lin, Kai Wang, Justin Snider, Sally Wen, Lina M. Obeid, Yusuf A. Hannun, Cungui Mao

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 agingrelated upregulation of SBs in yeast and a reduction in CLS. With the proteomicsbased 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.

Original languageEnglish (US)
Pages (from-to)21124-21144
Number of pages21
JournalOncotarget
Volume7
Issue number16
DOIs
StatePublished - Apr 19 2016
Externally publishedYes

Keywords

  • Aging
  • Gerotarget
  • Mitochondria
  • Sphingoid bases
  • Sphingolipids
  • Yeast

ASJC Scopus subject areas

  • Oncology

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