The ER tethers tightly to mitochondria and the mitochondrial protein FUNDC1 recruits Drp1 to ER-mitochondria contact sites, subsequently facilitating mitochondrial fission and preventing mitochondria from undergoing hypoxic stress. However, the mechanisms by which the ER modulates hypoxia-induced mitochondrial fission are poorly understood. Here, we show that USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and promotes hypoxia-induced mitochondrial division. In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP-binding and hydrolysis activities, thereby promoting mitochondrial division. Our findings reveal a unique hypoxia response pathway mediated by an ER protein that regulates mitochondrial dynamics.
USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites
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Peiyuan Chai, Yiru Cheng, Chuyi Hou, Lei Yin, Donghui Zhang, Yingchun Hu, Qingzhou Chen, Pengli Zheng, Junlin Teng, Jianguo Chen; USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites. J Cell Biol 5 July 2021; 220 (7): e202010006. doi: https://doi.org/10.1083/jcb.202010006
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