Figure 1.
Two models for formation of the apoptotic pore in the outer mitochondrial membrane.
In the conventional model, proapoptotic BCL-2 family members are the only molecules implicated in pore formation, with BH3-only proteins promoting conversion of BAX from an inactive monomeric state to form a multimeric BAX channel structure that acts as purely proteinaceous apoptotic pore. The extended model, supported by Newmeyer and colleagues, proposes that the apoptotic pore is regulated by the concerted action of proapoptotic BCL-2 family members together with membrane-remodeling factors (MRF) in the outer mitochondrial membrane. In this model, BH3-only proteins act in concert with MRF to promote the BAX-driven formation of a lipid-containing apoptotic pore. MRF might operate by generating membrane curvature, which could lead to BAX accumulation at this specific membrane microdomain, and/or could cause membrane stress that facilitates formation of a lipidic pore. MRF may be one or more proteins, but could potentially be a lipid, or a combination of proteins and lipids.