Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation

Wei Li, Qi Long, Hao Wu, Yanshuang Zhou, Lifan Duan, Hao Yuan, Yingzhe Ding, Yile Huang, Yi Wu, Jinyu Huang, Delong Liu, Baodan Chen, Jian Zhang, Juntao Qi, Shiwei Du, Linpeng Li, Yang Liu, Zifeng Ruan, Zihuang Liu, Zichao Liu, Yifan Zhao, Jianghuan Lu, Junwei Wang, Wai-Yee Chan and Xingguo Liu ()
Additional contact information
Wei Li: Chinese Academy of Sciences; Guangzhou Medical University
Qi Long: Chinese Academy of Sciences; Guangzhou Medical University
Hao Wu: Chinese Academy of Sciences; Guangzhou Medical University
Yanshuang Zhou: Chinese Academy of Sciences; Guangzhou Medical University
Lifan Duan: Chinese Academy of Sciences; Guangzhou Medical University
Hao Yuan: Chinese Academy of Sciences; Guangzhou Medical University
Yingzhe Ding: Chinese Academy of Sciences
Yile Huang: Chinese Academy of Sciences
Yi Wu: Chinese Academy of Sciences; Guangzhou Medical University
Jinyu Huang: Chinese Academy of Sciences; Guangzhou Medical University
Delong Liu: Chinese Academy of Sciences; Guangzhou Medical University
Baodan Chen: Chinese Academy of Sciences; Guangzhou Medical University
Jian Zhang: Chinese Academy of Sciences; Guangzhou Medical University
Juntao Qi: Chinese Academy of Sciences; Guangzhou Medical University
Shiwei Du: Chinese Academy of Sciences; Guangzhou Medical University
Linpeng Li: Chinese Academy of Sciences; Guangzhou Medical University
Yang Liu: Chinese Academy of Sciences; Guangzhou Medical University
Zifeng Ruan: Chinese Academy of Sciences; Guangzhou Medical University
Zihuang Liu: Chinese Academy of Sciences; Guangzhou Medical University
Zichao Liu: Chinese Academy of Sciences; Guangzhou Medical University
Yifan Zhao: Chinese Academy of Sciences
Jianghuan Lu: Chinese Academy of Sciences; Guangzhou Medical University
Junwei Wang: Chinese Academy of Sciences; Guangzhou Medical University
Wai-Yee Chan: The Chinese University of Hong Kong
Xingguo Liu: Chinese Academy of Sciences; Guangzhou Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35199-0

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