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Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-x  L  , an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-x  L   interaction  in vivo  and  in vitro . Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-x  L   interaction. Our data suggest that Mff primes Drp1 binding to Bcl-x  L   at the mitochondria and that Mff and Bcl-x  L   can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-x  L   interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-x  L   interaction. Expressing a Bcl-x  L   mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-x  L   interaction that contributes to cell death following ischemia.

SENP3 Promotes an Mff-Primed Bcl-xL-Drp1 Interaction Involved in Cell Death Following Ischemia