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

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.

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

“…An aging-induced decrease in nucleocytoplasmic acetyl-CoA levels could also contribute to the decreased histone H4K5 acetylation that occurs in aged worms. Consistent with this hypothesis, mitochondrial ETC dysfunction during larval development has been shown to decrease acetyl-CoA levels in C. elegans [ 386 ] and ETC dysfunction is a major phenotype of C. elegans aging [ 387 ]. Proteomics data has shown that the level of acetyl-CoA synthetase ACS-19, homologous to human ACSS2, decreases in post-reproductive worms and this decrease in ACS-19 abundance was delayed in long-lived daf-2 mutant worms [ 385 ].…”

“…Mitochondrial dysfunction during larval development was shown to result in decreased nucleocytoplasmic acetyl-CoA levels that decreased histone acetylation. The decreased level of acetyl-CoA was required for the proper activation of the UPR mt transcriptional response [ 386 ]. Adding back metabolites during the larval development that restored acetyl-CoA levels prevented induction of the UPR mt and lifespan extension.…”

Epigenetic codes of mitochondrial homeostasis

“…It will be interesting to understand how these epigenetic marks coordinate with others to control mitochondrial homeostasis. In addition, two recent studies identified that histone deacetylase HDA-1, the catalytic component of nucleosome remodeling and deacetylase (NuRD) complex, is required for UPR mt activation 13,14 . It has been proposed that mitochondrial dysfunction may limit the availability of acetyl-CoA and that the NuRD complex or HDA-1 removes the acetyl moiety from histones, feeding additional acetyl-CoA into metabolic reactions.…”

Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60

“…Dissection and fixation were carried out by freeze-crack method 84 . Worms were dissected in M9 buffer on a polylysine-coated slide.…”

“…We used at least 30 worms in each sample for DAPI staining and intestinal nuclei from more than 10 worms were selected and quantified for nuclear size 84 .…”