The effect of Ca2+ and acyl coenzyme A:lysophospholipid acyltransferase inhibitors on permeability properties of the liver mitochondrial inner membrane.

We have reported previously that a number of metabolites and toxins which cause Ca2+ release from mitochondria do so by increasing the permeability of the inner membrane. The metabolic basis of this permeability change is proposed to be perturbation of a phospholipid deacylation-reacylation cycle which results in an accumulation of free fatty acids and lysophospholipids (see Broekemeier, K. M., Schmid, P. C., Schmid, H. H. O., and Pfeiffer, D. R. (1985) J. Biol. Chem. 260, 105-113 and references therein). This hypothesis predicts that inhibitors of acyl-CoA:lysophospholipid acyltransferase would be among those agents which increase membrane permeability and that their effects on permeability could occur in the absence of pyridine nucleotide oxidation or of an accumulation of glutathione disulfide. The hypolipidemic drugs WY-14643 and clofibric acid inhibit the mitochondrial acyl-CoA:lysophospholipid acyltransferase and have the predicted effects on mitochondrial permeability properties. The development of increased permeability due to WY-14643 and clofibric acid requires accumulated Ca2+ specifically, is sensitive to inhibitors of phospholipase A2, and results in a pattern of solute release and swelling which is typical of other Ca2+-releasing agents. Neither agent promotes pyridine nucleotide nor sulfhydryl glutathione oxidation in the absence of Ca2+. In addition, the swelling response to hypolipidemic drugs is not significantly inhibited by dithiothreitol. In the presence of Ca2+, both agents promote an accumulation of free fatty acids. The composition of these lipid degradation products suggests that mitochondria treated with hypolipidemic drugs retain an active lysophospholipase whereas this enzyme is inactivated by Ca2+-releasing agents which alter mitochondrial sulfhydryl groups.