title: Differential mechanisms of induction of the mitochondrial permeability transition by quinones of varying chemical reactivities.
abstract: A nonspecific increase in permeability of the inner mitochondrial membrane is implicated in the mechanism of cell killing by a number of structurally diverse agents possessing vastly different chemical reactivities. The objective of this investigation was to distinguish the mechanisms by which quinones of varying redox cycling and arylating reactivities induce this mitochondrial permeability transition in vitro. All of the naphthoquinones examined caused a dose-dependent release of calcium from hepatic mitochondria. Associated with this was the calcium-dependent depolarization of membrane potential and mitochondrial swelling. For substituted naphthoquinones, 2-methyl-, 2,3-dimethyl-, and 2,3-dimethoxy-1, 4-naphthoquinone, induction of the mitochondrial permeability transition correlated with the rate of mitochondrial redox cycling and was strongly inhibited by cyclosporine A. In contrast, unsubstituted 1,4-naphthoquinone induced the permeability transition at concentrations where redox cycling was minimal. Induction of the permeability transition by 1,4-benzoquinone, which does not redox cycle, required that the mitochondria be preloaded with calcium and was not inhibited by cyclosporine A. With benzoquinone, the initiating event was a calcium-independent depolarization of mitochondrial membrane potential. In summary, the evidence indicates that redox cycling naphthoquinones induce the mitochondrial permeability transition by altering the regulation of the cyclosporine A-sensitive pore. In contrast, arylating quinones directly depolarize the mitochondrial membrane which, depending on the availability of matrix calcium, may be expressed as a cyclosporine A-insensitive permeability transition. These results reveal distinct mechanisms for inducing the mitochondrial permeability transition in vitro by quinones of varying chemical reactivities, which may be manifested as different mechanisms of cell killing.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Minnesota, Duluth 55812, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Henry
authors.forename: K B
authors.initials: KB
authors.lastname: Wallace
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009285:Naphthoquinones / Q000494:pharmacology; D010084:Oxidation-Reduction; D010539:Permeability; D011809:Quinones / Q000494:pharmacology*; D051381:Rats
chemical_list: D009285:Naphthoquinones; D011809:Quinones; D016572:Cyclosporine; D002118:Calcium