Mitochondrial Shape Governs BAX-Induced Membrane Permeabilization and Apoptosis

Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX requires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mitochondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, a GTPase involved in mitochondrial fusion, establishes a mitochondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAXα9·membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis. [Display omitted] •A proapoptotic BCL-2 repertoire containing BIM, PUMA, and BAX initiates MOMP•BAX-dependent membrane permeabilization exhibits mitochondrial size requirements•Mitochondrial membrane shape directly regulates BAX alpha helix 9 to induce MOMP•Mitochondrial hyperfission can be pharmacologically reversed to promote apoptosis Activated BAX targets the outer mitochondrial membrane (OMM) to initiate apoptosis, but a mechanistic role for the OMM in BAX function remains unknown. Here, Renault et al. demonstrate that mitochondrial shape directly impacts the ability of BAX alpha helix 9 to mobilize, interact with mitochondria, and initiate apoptosis.