Mitochondrial permeabilization: from lethality to vitality

Most apoptotic cell death events in the body occur via engagement of the mitochondrial pathway of apoptosis. This signaling pathway involves the regulated release, by members of the BCL2 protein family, of mitochondrial proteins following mitochondrial outer membrane permeabilization (MOMP). This in turn activates caspase proteases, generally leading to rapid destruction of the cell. However, recent reports have demonstrated that MOMP in the absence of full-blown caspase activation can have unexpected and detrimental effects. Here, we consider the mitochondrial pathway of apoptosis, how it came to be, and its place in the cell’s innate immune and cell death pathways. We then discuss two unexpected consequences of MOMP in the absence of cell death: activation of innate immune pathways via cytosolic DNA sensing and induction of DNA damage and cellular transformation