The role of mitochondria in apoptosis.

It has recently become apparent that mitochondria play a pivotal role in the process of cell death. In the absence of adenosine 5'-triphosphate (ATP) cells die by necrosis, but if sufficient ATP is available, a cascade of changes is initiated that lead to a much more orderly process of cell death (apoptosis). In addition to providing energy to the cell, mitochondria serve to sequester Ca(2+). Excessive accumulation of Ca(2+) leads to the formation of reactive oxygen species, together with the opening of the mitochondrial permeability transition pore, which depolarizes the mitochondria and leads to mitochondrial swelling. This may also provide a mechanism for the release of cytochrome c from the intermembrane space, although it is clear that there are probably other mechanisms also. Cytochrome c normally functions as part of the respiratory chain, but when released into the cytosol it becomes a critical component of the apoptosis execution machinery, where it activates caspases (cysteine aspartate proteases) and (if ATP is available) causes apoptotic cell death. The regulation of mitochondrial function by proteins related to Bcl-2 is also discussed, together with the prospects for the development of new therapies for disorders associated with cell death.