Abstract

Mild mitochondrial stress experienced early in life can have beneficial effects on the life span of organisms through epigenetic regulations. Here, we report that acetyl-coenzyme A (CoA) represents a critical mitochondrial signal to regulate aging through the chromatin remodeling and histone deacetylase complex (NuRD) in Caenorhabditis elegans. Upon mitochondrial stress, the impaired tricarboxylic acid cycle results in a decreased level of citrate, which accounts for reduced production of acetyl-CoA and consequently induces nuclear accumulation of the NuRD and a homeodomain-containing transcription factor DVE-1, thereby enabling decreased histone acetylation and chromatin reorganization. The metabolic stress response is thus established during early life and propagated into adulthood to allow transcriptional regulation for life-span extension. Furthermore, adding nutrients to restore acetyl-CoA production is sufficient to counteract the chromatin changes and diminish the longevity upon mitochondrial stress. Our findings uncover the molecular mechanism of the metabolite-mediated epigenome for the regulation of organismal aging.

Highlights

  • Metabolic homeostasis and aging are intimately linked [1]

  • Previous work has established that mitochondrial perturbations induce nuclear redistribution of DVE-1, a transcription factor (TF) that is essential for the UPRmt in C. elegans [11, 16]

  • The role of the nucleosome remodeling and histone deacetylase (NuRD) complex in the regulation of DVE-1 nuclear localization upon mitochondrial stress was further verified in animals with CRISPR-Cas9–mediated GFP knock-in at the locus of endogenous dve-1 C terminus. lin-40 mutants showed a lower level of dve-1::gfp signal in the intestinal nuclei compared to wild-type (WT) control animals under cco-1 RNA interference (RNAi) conditions (Fig. 1F)

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Summary

Introduction

Metabolic homeostasis and aging are intimately linked [1]. The cellular processes that respond to metabolic stress will influence the bioenergetic status of the cells, affecting the fitness of the entire organism. Metabolic stress in early life appears to be capable of restructuring chromatin, leaving a durable epigenetic change that may even influence the aging process [2]. A regulatory center for these epigenetic changes lies in the mitochondria [3]. Continuous communication between mitochondria and the nucleus allows cells and organisms to integrate nutrient availability and energy demand to ensure metabolic homeostasis [5]

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