Loss of SUR2 alters the composition of ceramides and shortens chronological lifespan of Saccharomyces cerevisiae.

Abstract

Sphingolipids are crucial components of cell membranes and serve as important signaling molecules. Ceramide, as the central hub of sphingolipid metabolism, plays a significant role in various biological processes, including the cell cycle, apoptosis, and cellular aging. Alterations in sphingolipid metabolism are implicated in cellular aging, however, the specific sphingolipid components and intrinsic mechanisms that mediate this process remain largely uncharacterized. In this study, we established a targeted sphingolipidomics approach and employed LC-MS/MS to quantitatively analyze changes in ceramide levels during chronological aging and in sur2Δ strains, aiming to elucidate the role of ceramides in regulating chronological lifespan. Our study revealed that in Saccharomyces cerevisiae, the C4 hydroxylase Sur2 and its product, phytoceramide, increase during chronological aging. While the loss of SUR2 function leads to a near-complete loss of phytoceramides and an accumulation of dihydroceramides, resulting in a significant reduction of total ceramide content to about half of that in wild-type cells. This ceramide profile alteration impairs both mitochondrial morphology and function, ultimately shortening the chronological lifespan. The knockout of SIT4 restores mitochondrial morphology and function, and rescues the chronological lifespan of SUR2-deficient yeast. Our findings highlight the critical role of dihydroceramide and phytoceramide in chronological aging in yeast and suggest that an imbalance between these two metabolites may trigger downstream ceramide signaling pathways. These insights could help elucidate potential mechanisms through which ceramide imbalance contributes to disease development in higher organisms.