Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms

Author:

Alfatah Mohammad1,Lim Jolyn Jia Jia1,Zhang Yizhong1,Naaz Arshia2,Trishia Cheng Yi Ning1,Yogasundaram Sonia1,Faidzinn Nashrul Afiq1,Jovian Jing Lin1,Eisenhaber Birgit123,Eisenhaber Frank1234

Affiliation:

1. Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)

2. Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)

3. LASA – Lausitz Advanced Scientific Applications gGmbH

4. School of Biological Sciences (SBS), Nanyang Technological University (NTU)

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 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.

Publisher

eLife Sciences Publications, Ltd

Reference73 articles.

1. Geroscience: Linking aging to chronic disease,2014

2. The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates;Article,2018

3. Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies;JAMA - Journal of the American Medical Association,2018

4. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes,2016

5. You have come a long way baby: Five decades of research on the biology of aging from the perspective of a researcher studying aging;Journals of Gerontology - Series A Biological Sciences and Medical Sciences,2021

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3