Mitochondria and cell death: outer membrane permeabilization and beyond

Mitochondrial outer membrane permeabilization (MOMP) is a crucial event for most apoptotic pathways. MOMP leads to the release of mitochondrial intermembrane space (IMS) proteins, such as cytochrome c, that promote caspase activation and apoptosis.Mitochondrial outer membrane integrity is dynamically regulated through interactions between pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family.The pro-apoptotic BCL-2 proteins BCL-2-associated X protein (BAX) and BCL-2 antagonist or killer (BAK) are required for MOMP, although how they permeabilize the mitochondrial outer membrane remains unresolved.Following MOMP, the mitochondrial release of certain IMS proteins can be further regulated.Caspase activity can also be regulated post-MOMP by many different means, both at the level of apoptosome formation and at caspase 9 and executioner caspase activity.MOMP generally commits a cell to death, irrespective of caspase activity, through a process termed caspase-independent cell death (CICD). Exactly how CICD occurs is unclear, but it involves the loss of mitochondrial function.Under some circumstances, cells can survive following MOMP. Cell survival under these conditions requires a pool of mitochondria that remain intact following MOMP. Survival is promoted by glycolysis and autophagy.