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Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan
Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with...
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Published in: | GeroScience 2023-08, Vol.45 (4), p.2161-2178 |
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container_title | GeroScience |
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creator | Phua, Cheryl Zi Jin Zhao, Xiaqing Turcios-Hernandez, Lesly McKernan, Morrigan Abyadeh, Morteza Ma, Siming Promislow, Daniel Kaeberlein, Matt Kaya, Alaattin |
description | Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain’s proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes. |
doi_str_mv | 10.1007/s11357-023-00796-4 |
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subjects | Actin Biomedical and Life Sciences Cell Biology Cell culture Eukaryotes Geriatrics/Gerontology Humans Life Sciences Life span Longevity - genetics Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondrial DNA Molecular Medicine Original Article Phenotype Phenotypes Proteasomes Proteome - genetics Proteome - metabolism Proteomes Saccharomyces cerevisiae - genetics |
title | Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan |
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