Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.

多能干细胞在再生医学和发育生物学研究中具有广阔前景。据报道，线粒体代谢物，包括三羧酸 (TCA) 循环中间体，在多能性中起着关键作用。在这里，我们展示了包括 Pdha1、Pcb、Aco2、Cs、Idh3a、Ogdh、Sdha 和 Mdh2 在内的 TCA 循环酶在体细胞重编程、启动到初始转换和全能性获得过程中转移到细胞核。核定位的 TCA 循环酶 Pdha1、Pcb、Aco2、Cs、Idh3a 促进体细胞重编程和致敏到幼稚的转变。此外，核定位的 TCA 循环酶，特别是核靶向 Pdha1，促进多能干细胞中的 2 细胞程序。从机制上讲，核 Pdha1 增加了细胞核中的乙酰辅酶 A 和代谢物池，通过增强组蛋白 H3 乙酰化导致多能性基因的染色质重塑。我们的结果揭示了线粒体 TCA 循环酶在多能性表观遗传调控中的重要作用，构成多能性获得的不同状态下的线粒体到细胞核逆行信号模式。