Open AccessAging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function
Author(s) -
Jae Kyo Yi,
Ruijuan Xu,
Eunmi Jeong,
Izolda Mileva,
JeanPhilip Truman,
ChihLi Lin,
Kai Wang,
Justin Snider,
Sally Wen,
Lina M. Obeid,
Yusuf A. Hannun,
Cungui Mao
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.8195
Subject(s) - mitochondrion , yeast , downregulation and upregulation , microbiology and biotechnology , mitophagy , biology , biochemistry , stable isotope labeling by amino acids in cell culture , proteomics , sphingolipid , saccharomyces cerevisiae , chemistry , gene , apoptosis , autophagy
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.