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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.
Cellular metabolism is important in pluripotency and cell fate regulation. Here, authors observe chromatin remodeling followed by TCA enzyme translocation from the mitochondria to the nucleus, demonstrating pluripotency regulation by mitochondria to nucleus retrograde signaling.
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1 Chinese Academy of Sciences; Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072); Chinese Academy of Sciences, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419)
2 Chinese Academy of Sciences; Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072); Chinese Academy of Sciences, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.9227.e) (ISNI:0000000119573309)
3 Chinese Academy of Sciences, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Hong Kong SAR, China (GRID:grid.9227.e) (ISNI:0000000119573309)
4 Chinese Academy of Sciences; Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072)
5 Chinese Academy of Sciences, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.9227.e) (ISNI:0000000119573309)
6 The Chinese University of Hong Kong, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, Hong Kong SAR, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482)
7 Chinese Academy of Sciences; Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072); Chinese Academy of Sciences, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Hong Kong SAR, China (GRID:grid.9227.e) (ISNI:0000000119573309)