A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation
A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation
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DOI：
10.1016/j.cell.2014.04.046
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发表时间：
2014-07-03
期刊：
影响因子：
64.5
通讯作者：
Michelakis, Evangelos D.
中科院分区：
文献类型：
--
作者：
Sutendra, Gopinath;Kinnaird, Adam;Michelakis, Evangelos D.
DNA的转录、复制和修复是由组蛋白乙酰化调控的，这一过程需要乙酰辅酶a （CoA）的产生。在这里，我们发现线粒体丙酮酸脱氢酶复合物（PDC）的所有亚基也存在于哺乳动物细胞核中并发挥作用。我们发现，在分离的功能性细胞核中，敲低核PDC降低了乙酰辅酶a的重新合成和核心组蛋白的乙酰化。核PDC水平以细胞周期依赖的方式增加，并响应血清、表皮生长因子或线粒体应激；这伴随着线粒体PDC水平的相应下降，表明从线粒体到细胞核的易位。抑制核PDC降低了对G1-S期进展和S期标志物表达重要的组蛋白上特定赖氨酸残基的乙酰化。线粒体PDC向细胞核的动态易位为组蛋白乙酰化和表观遗传调控所需的核乙酰辅酶a合成提供了一条途径。
DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis of acetyl-CoA and acetylation of core histones. Nuclear PDC levels increased in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress; this was accompanied by a corresponding decrease in mitochondrial PDC levels, suggesting a translocation from the mitochondria to the nucleus. Inhibition of nuclear PDC decreased acetylation of specific lysine residues on histones important for G1-S phase progression and expression of S phase markers. Dynamic translocation of mitochondrial PDC to the nucleus provides a pathway for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.