Uncharacterized yeast geneYBR238C,an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging viaHAP4- andRMD9-dependent mechanisms

Abstract

AbstractUncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared gene sets involved in regulating the lifespan ofSaccharomyces cerevisiae(a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set,YBR238Cstood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show thatYBR238Cand its paralogueRMD9oppositely affect mitochondria and aging.YBR238Cdeletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect ofYBR238Cis largely explained byHAP4- andRMD9-dependent mechanisms. Further, we find that genetic or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion ofYBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (theTORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby,YBR238Cis an effector of TORC1 modulating mitochondrial function.