State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100093, China.
Sci Adv. 2020 Jul 31;6(31):eabb2529. doi: 10.1126/sciadv.abb2529. eCollection 2020 Jul.
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 . 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.
早期经历轻度线粒体应激可以通过表观遗传调控对生物体的寿命产生有益影响。在这里，我们报告说，乙酰辅酶 A（CoA）代表了一种关键的线粒体信号，可通过染色质重塑和组蛋白去乙酰化酶复合物（NuRD）来调节衰老。在受到线粒体应激时，三羧酸循环受损会导致柠檬酸水平降低，这会导致乙酰辅酶 A 的产生减少，并促使 NuRD 和含有同源域的转录因子 DVE-1 核内积累，从而导致组蛋白乙酰化和染色质重排减少。因此，代谢应激反应在生命早期建立，并传播到成年期，以允许转录调节来延长寿命。此外，添加营养物质以恢复乙酰辅酶 A 的产生足以抵消染色质变化，并减少线粒体应激时的寿命。我们的研究结果揭示了代谢物介导的表观基因组调控生物体衰老的分子机制。
