Death upon a kiss: mitochondrial outer membrane composition and organelle communication govern sensitivity to BAK/BAX-dependent apoptosis.

For stressed cells to induce the mitochondrial pathway of apoptosis, a cohort of pro-apoptotic BCL-2 proteins must collaborate with the outer mitochondrial membrane to permeabilize it. BAK and BAX are the two pro-apoptotic BCL-2 family members that are required for mitochondrial outer membrane permeabilization. While biochemical and structural insights of BAK/BAX function have expanded in recent years, very little is known about the role of the outer mitochondrial membrane in regulating BAK/BAX activity. In this review, we will highlight the impact of mitochondrial composition (both protein and lipid) and mitochondrial interactions with cellular organelles on BAK/BAX function and cellular commitment to apoptosis. A better understanding of how BAK/BAX and mitochondrial biology are mechanistically linked will likely reveal novel insights into homeostatic and pathological mechanisms associated with apoptosis.