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

Aiswarya Baruah,Siu Sylvia Lee,Mathew Hall,Siegfried Hekimi,Jie Yuan,W Brent Derry,Sarah Gordon,Hsinwen Chang,Ludmila L Shtessel,Callista Yee,Erik Johnson

doi:10.1371/journal.pgen.1004097

Aiswarya Baruah, Siu Sylvia Lee + Show 9 more

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https://doi.org/10.1371/journal.pgen.1004097

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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.

Highlights

Mitochondria are major sites of numerous metabolic processes, in particular electron transport and ATP production, and are essential for life
Our results indicate that CEP-1 is a critical mediator of the lifespan of several mitochondrial mutants, suggesting that CEP-1 plays a central role in sensing mitochondrial distress and coordinating physiological outcomes
Previous results suggested that cep-1 is required for the lifespan extension associated with mild mitochondrial dysfunction and the shortened lifespan associated with severe mitochondrial dysfunction [25]

Summary

Introduction

Mitochondria are major sites of numerous metabolic processes, in particular electron transport and ATP production, and are essential for life. Mitochondria play central roles in aging and disease [1]. In model organisms such as worms, flies, and mice, specific point mutations or RNAi knockdowns directly affecting the electron transport chain (ETC) result in varying effects on development and longevity, ranging from developmental arrest and shortened survival to extended lifespan. An emerging model posits that a moderate reduction in mitochondrial ETC function can lead to compensatory responses that lengthen lifespan [2,3,4,5], whereas a more severe reduction in mitochondrial ETC function, beyond an innate threshold, will lead to developmental arrest and/or early death [6,7]. How different degrees of mitochondrial dysfunction result in opposing effects on longevity remains largely unknown

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