NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level
复制标题
NuRD 通过响应乙酰辅酶 A 水平的染色质重塑介导线粒体应激诱导的长寿
DOI：
10.1126/sciadv.abb2529
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发表时间：
2020-07-01
期刊：
影响因子：
13.6
通讯作者：
Tian, Ye
中科院分区：
文献类型：
--
作者：
Zhu, Di;Wu, Xueying;Tian, Ye
在生命早期经历的轻微线粒体应激可以通过表观遗传调节对生物体的寿命产生有益的影响。在这里，我们报道了乙酰辅酶A(CoA)是线虫通过染色质重塑和组蛋白脱乙酰酶复合体(NuRD)调节衰老的关键信号。在线粒体应激时，受损的三羧酸循环导致柠檬酸水平下降，这是乙酰辅酶A产生减少的原因，从而导致NuRD和含有同源结构域的转录因子DVE-1的核积聚，从而使组蛋白乙酰化和染色质重组减少。因此，代谢应激反应是在生命早期建立的，并传播到成年，以允许转录调节以延长寿命。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的变化，并降低线粒体应激的寿命。我们的发现揭示了代谢物介导的表观基因组调节生物衰老的分子机制。
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.