Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction

Leukotoxin, a cytochrome P450-derived epoxide of linoleic acid, has been im plicated as a causative factor in acute respiratory distress syndrome. Conv ersion of this fatty acid epoxide to leukotoxin diol by epoxide hydrolase h as been hypothesized as the critical activation step in leukotoxin-induced cellular toxicity. In both human and insect cells, we observed that leukoto xin diol causes acute cellular toxicity and that cyclosporin A, an inhibito r of the mitochondrial permeability transition, ameliorates leukotoxin diol -associated toxicity. To evaluate mitochondria as a target of leukotoxin di ol, multiple aspects of mitochondrial integrity were evaluated in both cell - and organelle-based assays. Leukotoxin diol specifically activated the mi tochondrial permeability transition, resulting in release of cytochrome c a nd subsequent cell death. Pretreatment with cyclosporin A inhibited these e ffects and, furthermore, limited in vivo toxicity. While the mechanisms und erlying leukotoxin-mediated toxicity remain to be fully elucidated, the obs ervation that leukotoxin diol disrupts mitochondrial function specifically through activation of the mitochondrial permeability transition suggests at least one mechanism through which leukotoxin diol may exert its activity i n physiological contexts. (C) 2001 Academic Press.