Cell Metabolism
Volume 28, Issue 6, 4 December 2018, Pages 935-945.e5
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Short Article
Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming

https://doi.org/10.1016/j.cmet.2018.08.001Get rights and content
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Highlights

  • mPTP exhibits short-term opening during the early phase of reprogramming

  • Early-phase mPTP opening enhances reprogramming

  • mPTP opening decreases H3K9me2/H3K27me3 methylation, mediated by PHF8

  • PHF8 activity is enhanced via mitochondrial ROS and miR-101c

Summary

Reprogramming of somatic cells to induced pluripotent stem cells reconfigures chromatin modifications. Whether and how this process is regulated by signals originating in the mitochondria remain unknown. Here we show that the mitochondrial permeability transition pore (mPTP), a key regulator of mitochondrial homeostasis, undergoes short-term opening during the early phase of reprogramming and that this transient activation enhances reprogramming. In mouse embryonic fibroblasts, greater mPTP opening correlates with higher reprogramming efficiency. The reprogramming-promoting function of mPTP opening is mediated by plant homeodomain finger protein 8 (PHF8) demethylation of H3K9me2 and H3K27me3, leading to reduction in their occupancies at the promoter regions of pluripotency genes. mPTP opening increases PHF8 protein levels downstream of mitochondrial reactive oxygen species production and miR-101c and simultaneously elevates levels of PHF8's cofactor, α-ketoglutarate. Our findings represent a novel mitochondria-to-nucleus pathway in cell fate determination by mPTP-mediated epigenetic regulation.

Keywords

histone lysine methylation
induced pluripotent stem cells
mitochondrial permeability transition pore
PHF8
reprogramming

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6

These authors contributed equally

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