title: Mitochondrial swelling and cytochrome c release: sensitivity to cyclosporin A and calcium.
abstract: The opening of mitochondrial membrane permeability transition (MPT) pores, which results in a cyclosporin A (CsA)-sensitive and Ca(2+)-dependent dissipation of the membrane potential (delta psi) and swelling (classical MPT), has been postulated to play an important role in the release of cytochrome c (Cyt.c) and also in apoptotic cell death. Recently, it has been reported that CsA-insensitive or Ca(2+)-independent MPT can be classified as non-classic MPT. Therefore, we studied the effects of apoptosis-inducing agents on mitochondrial functions with respect to their CsA-sensitivity and Ca(2+)-dependency. CsA-sensitive mitochondrial swelling, depolarization, and the release of Ca2+ and Cyt.c were induced by low concentrations of arachidonic acid, triiodothyronine (T3), or 6-hydroxdopamine but not by valinomycin and high concentrations of the fatty acid or T3. Fe2+/ADP and 2,2,-azobis-(2-amidinopropane) dihydrochloride (AAPH) induced swelling of mitochondria and the release of Ca2+ and Cyt.c were not coupled with depolarization or CsA-sensitivity while dibucaine-induced swelling occurred without depolarization, Cyt.c-release or by a CsA-sensitive mechanism. A protonophoric FCCP and SF-6847 induced depolarization and Ca(2+)-release occurred in a CsA-insensitive manner and failed to stimulate the release of Cyt.c. These results indicate that ambient conditions of mitochondria can greatly influence the state of membrane stability and that Cyt.c release may occur not only via a CsA-sensitive MPT but also by way of a CsA-insensitive membrane deterioration.
authors.affiliation: Institute of Medical Science, Kurashiki Medical Center, Kurashiki 710-8522, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kanno
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Shikibu
authors.initials: S
authors.lastname: Muranaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yano
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Utsumi
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Masayasu
authors.initials: M
authors.lastname: Inoue
authors.forename: Kozo
authors.initials: K
authors.lastname: Utsumi
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000493:pharmacokinetics*; D004789:Enzyme Activation / Q000187:drug effects; D008099:Liver / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003574:Cytochrome c Group; D016572:Cyclosporine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium