USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites

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.

Automated summary

The study demonstrates that the ER-resident deubiquitinase USP19 accumulates at ER-mitochondria contact sites under hypoxia, promoting hypoxia-induced mitochondrial fission by binding to and deubiquitinating FUNDC1, facilitating Drp1 oligomerization and activity. The findings reveal a unique hypoxia response pathway mediated by an ER protein regulating mitochondrial dynamics.