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• W4383347504 abstract "SUMMARY 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 wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TO RC1- MI tochondria- TO RC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function." @default.
• W4383347504 created "2023-07-07" @default.
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• W4383347504 date "2023-07-05" @default.
• W4383347504 modified "2023-09-29" @default.
• W4383347504 title "Uncharacterized yeast gene<i>YBR238C,</i>an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via<i>HAP4</i>- and<i>RMD9</i>-dependent mechanisms" @default.
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• W4383347504 doi "https://doi.org/10.1101/2023.07.04.547743" @default.
• W4383347504 hasPublicationYear "2023" @default.
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