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

Abstract

Uncovering 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 of Saccharomyces 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, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralogue RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-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 of YBR238C) 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 the wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.

Curcumin extends the lifespan of aging postmitotic cells with mitochondrial dysfunction

“…Conversely, at the same chronological aging time points (day 5 and day 6), the survival rate of wildtype (DMSO control) remained at approximately 100% (Figures 2B and 2C). These results align with our previous findings, illustrating that mitochondrial dysfunction leads to accelerated aging and a shortened PoMiCL 44 . Remarkably, curcumin treatment prevents accelerated aging and enhances the PoMiCL of mitochondrial dysfunction pet100Δ mutant (Figures 2B and 2C).…”

“…In our previous study, we demonstrated that inducing mitochondrial dysfunction through chemical or genetic means accelerates cellular aging and reduces the lifespan of postmitotic cells 44 . Given the pivotal role of mitochondrial function in age-related diseases and the potential influence of curcumin on cellular aging, we explored the impact of curcumin on the lifespan of postmitotic cells deficient in mitochondrial function during chronological aging.…”

“…TORC1 senses nutrients and is closely linked to the growth and proliferation of cells. Previously, we discovered that inhibiting TORC1 can prevent the accelerated cellular aging associated with mitochondrial dysfunction 44 . Interestingly, mutants with mitochondrial dysfunction were found to be resistant to rapamycin-induced cellular growth inhibition 44 .…”

“…Previously, we discovered that inhibiting TORC1 can prevent the accelerated cellular aging associated with mitochondrial dysfunction 44 . Interestingly, mutants with mitochondrial dysfunction were found to be resistant to rapamycin-induced cellular growth inhibition 44 . Furthermore, mutants such as pet100Δ and rmd9Δ also showed resistance to the growth-inhibiting effects of curcumin (Figure 4A).…”