Membrane Remodeling Induced by the Dynamin-Related Protein Drp1 Stimulates Bax Oligomerization

SummaryIn response to many apoptotic stimuli, oligomerization of Bax is essential for mitochondrial outer membrane permeabilization and the ensuing release of cytochrome c. These events are accompanied by mitochondrial fission that appears to require Drp1, a large GTPase of the dynamin superfamily. Loss of Drp1 leads to decreased cytochrome c release by a mechanism that is poorly understood. Here we show that Drp1 stimulates tBid-induced Bax oligomerization and cytochrome c release by promoting tethering and hemifusion of membranes in vitro. This function of Drp1 is independent of its GTPase activity and relies on arginine 247 and the presence of cardiolipin in membranes. In cells, overexpression of Drp1 R247A/E delays Bax oligomerization and cell death. Our findings uncover a function of Drp1 and provide insight into the mechanism of Bax oligomerization.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (128 K)Download as PowerPoint slideHighlights► Drp1 promotes tBid-induced Bax oligomerization by triggering membrane hemifusion ► Drp1 induces membrane hemifusion independently of its GTPase activity ► Cardiolipin is essential for Drp1-induced membrane hemifusion ► Drp1 mutants lacking membrane hemifusion activity delay Bax oligomerization in vivo