Mitochondrial iPLA2Activity Modulates the Release of Cytochromecfrom Mitochondria and Influences the Permeability Transition

Martha E. Gadd, Kimberly M. Broekemeier, Elliott D. Crouser, Jitendra Kumar, Gustav Graff, Douglas R. Pfeiffer
2006 Journal of Biological Chemistry  
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؉
more » ... 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. . 3 The abbreviations used are: iPLA 2 , Ca 2ϩ -independent phospholipase A 2 ; BEL, bromoenol lactone; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CsA, cyclosporin A; FAME, fatty acid methyl esters; FFA, free fatty acid(s); IMAC, inner membrane anion channel; Mes, 2-(N-morpholino)ethanesulfonic acid; HPLC, high pressure liquid chromatography. Downloaded from 4 Work in progress indicates that rat liver mitochondria do indeed contain a lysophospholipase activity, which exceeds the activity of the iPLA 2 . Nevertheless, it remains possible that low levels of lysophospholipids are present as a result of iPLA 2 activity and contribute to the consequences of activating that enzyme.
doi:10.1074/jbc.m510845200 pmid:16407316 fatcat:53ghe65f5fgsfngrqcdnmosmly