Mitochondrial iPLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition

The mitochondrial Ca2+-independent phospholipase A(2) is activated during energy-dependent Ca2+ accumulation under conditions where there is a sustained depression of the membrane potential. This activation is not dependent on induction of the mitochondrial permeability transition. Bromoenol lactone, which inhibits the phospholipase, is effective as an inhibitor of the transition, and this action can be overcome by low levels of exogenous free fatty acids. Apparently, activation of the Ca2+-independent phospholipase is a factor in the mechanisms by which depolarization and Ca2+ accumulation promote opening of the permeability transition pore. Sustained activity of the Ca2+-independent phospholipase A(2) promotes rupture of the outer mitochondrial membrane and spontaneous release of cytochrome c on a time scale similar to that of apoptosis occurring in cells. However, more swelling of the matrix space must occur to provoke release of a given cytochrome c fraction when the enzyme is active, compared with when it is inhibited. Through its effects on the permeability transition and release of intermembrane space proteins, the mitochondrial Ca2+-independent phospholipase A(2) may be an important factor governing cell death caused by necrosis or apoptosis.