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

// Jae Kyo Yi 1,2,3 , Ruijuan Xu 2,3 , Eunmi Jeong 2,3 , Izolda Mileva 2,3 , Jean-Philip Truman 2 , Chih-li Lin 1,2,3 , Kai Wang 2,3 , Justin Snider 1,2 , Sally Wen 2,3 , Lina M. Obeid 2,3,4 , Yusuf A. Hannun 2,3 and Cungui Mao 2,3 1 Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY, USA 2 Department of Medicine, Stony Brook University, Stony Brook, NY, USA 3 Stony Brook Cancer Center, Stony Brook, NY, USA 4 Northport Veterans Affairs Medical Center, Northport, NY, USA Correspondence to: Cungui Mao, email: // Keywords : sphingolipids, aging, yeast, sphingoid bases, mitochondria, Gerotarget Received : February 09, 2016 Accepted : March 04, 2016 Published : March 19, 2016 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.