title: CEP-1, the Caenorhabditis elegans p53 homolog, mediates opposing longevity outcomes in mitochondrial electron transport chain mutants.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Aiswarya
authors.initials: A
authors.lastname: Baruah
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Hsinwen
authors.initials: H
authors.lastname: Chang
authors.affiliation: Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mathew
authors.initials: M
authors.lastname: Hall
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gordon
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Ludmila L
authors.initials: LL
authors.lastname: Shtessel
authors.affiliation: Department of Biology, McGill University, Montréal, Quebec, Canada.
authors.forename: Callista
authors.initials: C
authors.lastname: Yee
authors.affiliation: Department of Biology, McGill University, Montréal, Quebec, Canada.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hekimi
authors.affiliation: Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: W Brent
authors.initials: WB
authors.lastname: Derry
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Siu Sylvia
authors.initials: SS
authors.lastname: Lee
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D008136:Longevity / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D045222:Electron Transport Chain Complex Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53