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.

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

“…P values were calculated by exact hypergeometric probability. [Note that small increase in lifespan by ftn-1/-2 knockdown was also observed previously (15,74).] See SI Appendix, Table S4 for additional lifespan data and detailed statistical analyses.…”

“…C. elegans smf-3, which is the ortholog of divalent metal transporter 1 (DMT1), plays a role in iron uptake in an HIF-1-dependent manner (25,44). C. elegans HIF-1 down-regulates ftn-1 and ftn-2, which are homologs of iron-storage protein ferritins that are required for reducing intracellular levels of free iron (25,44) and are partially required for the longevity of isp-1 mutants (15). By using quantitative RT-PCR, we confirmed that the mRNA levels of smf-3 were decreased by hif-1(ia4) mutations in isp-1 mutants (Fig.…”

“…Key genetic factors that mediate longevity caused by reduced mitochondrial respiration in C. elegans have been identified recently (10)(11)(12)(13)(14)(15)(16)(17). However, the mechanisms are not completely understood.…”

Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

“…To extend beyond RNAi based experiments, we examined activation of the HSR and stress resistance at day 2 of adulthood in animals with loss-of-function mutations in mitochondrial genes (Baruah et al, 2014; Feng et al, 2001; Lakowski and Hekimi, 1996; Walter et al, 2011; Butler et al, 2010). Long-lived isp-1(qm150), nuo-6(qm200), isp-1(qm150);ctb-1(qm189) , and clk-1(qm30) mutants, but not short-lived mev-1(kn1), gas-1(fc21) , and ucr-2.3(pk732) mutants, all exhibited a greater than 3 fold increase in median survival, a 2 – 4 fold increase in the levels of hsp-70, F44E5.4 , and hsp-16.11 mRNA, and a 2–3 fold increase in levels of HSP-16 protein compared to wild type worms following HS on day 2 of adulthood (Figures 2C-F and S2D).…”

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

“…Thus, factors other than HIF‐1 appear to contribute to the regulation of nhr‐57 expression and longevity. These factors may include transcription factors, DVE‐1, CEH‐23, and CEP‐1, which regulate longevity in response to inhibition of mitochondrial components (Durieux et al ., 2011; Walter et al ., 2011; Baruah et al ., 2014), because nhr‐57 is induced by impaired mitochondrial functions (Lee et al ., 2010). In addition, transcription factors, such as ELT‐3, EOR‐1, BLMP‐1, ALR‐1, PHA‐4, PQM‐1, SKN‐1, MDL‐1, and PES‐1, bind to the promoter region of nhr‐57 , based on modENCODE data analysis (Gerstein et al ., 2010; Van Nostrand & Kim, 2013).…”