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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Bibliographic Details
Published in:GeroScience 2023-08, Vol.45 (4), p.2161-2178
Main Authors: Phua, Cheryl Zi Jin, Zhao, Xiaqing, Turcios-Hernandez, Lesly, McKernan, Morrigan, Abyadeh, Morteza, Ma, Siming, Promislow, Daniel, Kaeberlein, Matt, Kaya, Alaattin
Format: Article
Language:English
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
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Summary: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.
ISSN:2509-2723
2509-2715
2509-2723
DOI:10.1007/s11357-023-00796-4