title: Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction.
abstract: Leukotoxin, a cytochrome P450-derived epoxide of linoleic acid, has been implicated as a causative factor in acute respiratory distress syndrome. Conversion of this fatty acid epoxide to leukotoxin diol by epoxide hydrolase has been hypothesized as the critical activation step in leukotoxin-induced cellular toxicity. In both human and insect cells, we observed that leukotoxin diol causes acute cellular toxicity and that cyclosporin A, an inhibitor of the mitochondrial permeability transition, ameliorates leukotoxin diol-associated toxicity. To evaluate mitochondria as a target of leukotoxin diol, multiple aspects of mitochondrial integrity were evaluated in both cell- and organelle-based assays. Leukotoxin diol specifically activated the mitochondrial permeability transition, resulting in release of cytochrome c and subsequent cell death. Pretreatment with cyclosporin A inhibited these effects and, furthermore, limited in vivo toxicity. While the mechanisms underlying leukotoxin-mediated toxicity remain to be fully elucidated, the observation 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 in physiological contexts.
authors.affiliation: Department of Entomology, University of California, Davis, California 95616, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Sisemore
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.forename: J C
authors.initials: JC
authors.lastname: Yang
authors.forename: D A
authors.initials: DA
authors.lastname: Thompson
authors.forename: C G
authors.initials: CG
authors.lastname: Plopper
authors.forename: G A
authors.initials: GA
authors.lastname: Cortopassi
authors.forename: B D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D018411:Spodoptera; D013229:Stearic Acids / Q000633:toxicity*
chemical_list: C120038:9,10-dihydroxy-12-octadecenoic acid; D013229:Stearic Acids; D016572:Cyclosporine