NuRD mediates mitochondrial stress–induced longevity via chromatin remodeling in response to acetyl-CoA level

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.