Arachidonic acid causes cell death through the mitochondrial permeability transition - Implications for tumor necrosis factor-alpha apoptotic signaling

We have investigated the effects of arachidonic and palmitic acids in isola ted rat liver mitochondria and in rat hepatoma MH1C1 cells. We show that bo th compounds induce the mitochondrial permeability transition (PT). At vari ance from palmitic acid, however, arachidonic acid causes a PT at concentra tions that do not cause PT-independent depolarization or respiratory inhibi tion, suggesting a specific effect on the PT pore. When added to intact MH1 C1 cells, arachidonic acid but not palmitic acid caused a mitochondrial PT in situ that was accompanied by cytochrome c release and rapidly followed b y cell death. All these effects of arachidonic acid could be prevented by c yclosporin A but not by the phospholipase A(2) inhibitor aristolochic acid. In contrast, tumor necrosis factor alpha caused phospholipid hydrolysis, i nduction of the PT, cytochrome c release, and cell death that could be inhi bited by both cyclosporin A and aristolochic acid. These findings suggest t hat arachidonic acid produced by cytosolic phospholipase A(2) may be a medi ator of tumor necrosis factor alpha cytotoxicity in situ through induction of the mitochondrial PT.