Apoptosis: unmasking the executioner

The execution phase of apoptosis is comprised of those processes that commit cells to apoptotic death. Many independent studies have implicated mitochondria as playing a critical role in apoptotic execution. The activation of caspase-3 and subsequent late stage degradative events are probably triggered by the release of proteins (such as cytochrome c) from the intermembrane space of mitochondria. The mechanisms responsible for this release are controversial but may include mitochondrial permeability transition and bcl-2-regulated swelling of the mitochondrial matrix. Two theoretical models of execution are discussed. It is important to note that some critical features of these models are largely based on data acquired from cell-free studies. Further studies with intact cells are urgently needed to test the physiological validity of these models.