CEP-1, the Caenorhabditis elegans p53 Homolog, Mediates Opposing Longevity Outcomes in Mitochondrial Electron Transport Chain Mutants

Author Summary Perturbing different components of the mitochondrial electron transport chain (ETC) can affect the lifespan of Caenorhabditis elegans in divergent ways. ETC dysfunction can either attenuate or extend C. elegans lifespan. Here we demonstrate that the C. elegans homolog of mammalian p53, CEP-1, is key in mediating differential survival of distinct ETC mutants. Inactivating cep-1 in two long-lived ETC mutants shortened their lifespans, whereas cep-1 deletion in two short-lived ETC mutants restored their lifespans. Because how CEP-1 does this is unknown, we compared the genome-wide expression profiles of the long-lived isp-1 and short-lived mev-1 ETC mutants upon cep-1 removal. We found that CEP-1 is able to differentially regulate a small subset of genes depending on the specific ETC mutations. We validated one of the genes, the iron transporter ferritin (ftn-1), to be an important target through which CEP-1 mediates distinct lifespan outcome in specific ETC mutants. We also identified numerous other candidate CEP-1 targets that merit future analysis, which will further elucidate how CEP-1 differentially responds to the distinct ETC dysfunction of various mitochondrial mutants. Our study provides new insights that will inform how mammalian p53, a critical tumor suppressor, might respond to mitochondrial and metabolic stresses. 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.