The mitochondrial Ca 2؉ -independent phospholipase A 2 is activated during energy-dependent Ca 2؉ 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 Ca 2؉ -independent phospholipase is a factor in the mechanisms by which depolarization and Ca 2؉ accumulation promote opening of the permeability transition pore. Sustained activity of the Ca 2؉ -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 Ca 2؉ -independent phospholipase A 2 may be an important factor governing cell death caused by necrosis or apoptosis.Mitochondria from rat liver and rabbit heart have been shown to contain a Ca 2ϩ -independent phospholipase A 2 (iPLA 2 ) 3 that has a molecular mass of ϳ80 kDa (1, 2). Like phospholipases of this type from other sources (3, 4), the mitochondrial enzyme is inactivated by bromoenol lactone (BEL), which acts through an activity-dependent mechanism, leading to a covalent modification within the active site (5). No physiological function of the iPLA 2 in mitochondria has been established, but it has been shown that pretreatment with BEL attenuates the loss of phospholipids that accompanies ischemia/reperfusion injury and reduces the size of infarcts by ϳ50% (2).The relationship between mitochondrial energetic status and iPLA 2 activity is an important factor to consider when contemplating potential physiological and pathophysiological roles of the enzyme. More specifically, activity is not seen in mitochondria that are respiring under state 4 conditions but is manifest upon the addition of uncoupler and is fully manifest following the development of inner membrane pores (1). The former property suggests that transient periods of deenergization might cause a transient activation of the iPLA 2 in vivo, with a resulting accumulation of free fatty acids in mitochondria. Such an accumulation could be of interest in many regards, including opening of the permeability transition pore, which is favored by low levels of these compounds (6 -8). Occurrence of the permeability transition leads to apoptosis in many cell types (9 -11), so scenarios arise in which the iPLA 2 contributes to the control of apoptosis by influencing the permeability transition and wherein the facilitative effects of depolarization on the transition (12, 13) might occur through activity of this enzyme...

These studies confirm that liver mitochondria are early targets of injury during endotoxemia and that inner and outer mitochondrial membrane damage occurs through different mechanisms. Inner mitochondrial membrane damage appears to relate to the mitochondrial permeability transition, whereas outer mitochondrial membrane damage can occur independent of the mitochondrial permeability transition. Preliminary evidence suggests that Bax may participate in lipopolysaccharide-induced outer mitochondrial membrane damage, but further investigations are needed to confirm this.