CEP-1, the Caenorhabditis elegans p53 homolog, mediates opposing longevity outcomes in mitochondrial electron transport chain mutants

• Published in: PLoS genetics Vol. 10; no. 2; p. e1004097
• Main Authors: Baruah, Aiswarya, Chang, Hsinwen, Hall, Mathew, Yuan, Jie, Gordon, Sarah, Johnson, Erik, Shtessel, Ludmila L, Yee, Callista, Hekimi, Siegfried, Derry, W Brent, Lee, Siu Sylvia
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2014; Public Library of Science (PLoS)
• Subjects: Aging; Animals; Biology; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Electron transport; Electron Transport Chain Complex Proteins - biosynthesis; Electron Transport Chain Complex Proteins - genetics; Experiments; Gene expression; Gene Expression Profiling; Gene mutations; Genetic aspects; Longevity - genetics; Mitochondria - genetics; Mitochondria - pathology; Mutation; Nematodes; Physiological aspects; Sequence Homology, Amino Acid; Transcriptome; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004097

Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the isp-1 and mev-1 mutants. Interestingly, this small group of differentially regulated genes are enriched for the "aging" Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in isp-1 and mev-1 mutants. We further focused on one of these differentially regulated genes, ftn-1, which encodes ferritin in C. elegans, and demonstrated that it specifically contributed to the extended lifespan of isp-1 mutant worms but did not affect the mev-1 mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.