MAPL SUMOylation of Drp1 Stabilizes an ER/Mitochondrial Platform Required for Cell Death

There has been evidence that mitochondrial fragmentation is required for apoptosis, but the molecular links between the machinery regulating dynamics and cell death have been controversial. Indeed, activated BAX and BAK can form functional channels in liposomes, bringing into question the contribution of mitochondrial dynamics in apoptosis. We now demonstrate that the activation of apoptosis triggers MAPL/MUL1-dependent SUMOylation of the fission GTPase Drp1, a process requisite for cytochrome c release. SUMOylated Drp1 functionally stabilizes ER/mitochondrial contact sites that act as hotspots for mitochondrial constriction, calcium flux, cristae remodeling, and cytochrome c release. The loss of MAPL does not alter the activation and assembly of BAX/BAK oligomers, indicating that MAPL is activated downstream of BAX/BAK. This work demonstrates how interorganellar contacts are dynamically regulated through active SUMOylation during apoptosis, creating a stabilized platform that signals cytochrome c release. [Display omitted] •MAPL and mitochondrial SUMOylation are required for an efficient cell death•MAPL SUMOylates Drp1 at the ER/mitochondria interface during apoptosis•SUMOylated Drp1 functionally stabilizes an ER/mitochondrial signaling platform•Ca2+ transfer from ER is required for cristae remodeling and cytochrome c release Prudent et al. show that MAPL SUMOylates Drp1 at the ER/mitochondria contact sites during cell death. This mitochondrial SUMOylation is involved in the stabilization of an ER/mitochondrial signaling platform required for mitochondrial constriction, calcium flux, cristae remodeling, and an efficient cytochrome c release downstream of BAX/BAK activation.