title: Silver ion induces a cyclosporine a-insensitive permeability transition in rat liver mitochondria and release of apoptogenic cytochrome C.
abstract: Various reagents are known to open the mitochondrial permeability pore (PTP) and induce a permeability transition (PT), releasing apoptogenic proteins from the intermembrane space and triggering apoptosis. In this study, we examined the effect of Ag(+), a known cytotoxic sulfhydryl-reactive heavy metal, on isolated rat liver mitochondria. The following results were obtained: (1) Upon addition, Ag(+) instantly induced mitochondrial swelling and acceleration of respiration. (2) Cyclosporine A, a specific inhibitor of classical PT, was ineffective against the effect of Ag(+), indicating that silver ions induced non-classic PT. (3) Sulfhydryl reagents such as reduced glutathione completely inhibited the effects of Ag(+) on the mitochondria. (4) Experimental results using polyethylene glycol indicated that Ag(+) induced opening of a pore in the inner mitochondrial membrane, which could be PTP of another open state or a distinct pore. (5) Electron microscopic analysis of mitochondria treated with Ag(+) showed a novel mitochondrial configuration that was apparently different from that of normal mitochondria or Ca(2+)-treated mitochondria. (6) Ag(+) also induced the release of apoptogenic cytochrome c in a CsA-insensitive but GSH-sensitive manner. These results suggest that Ag(+) promotes a nonclassical permeability increase in the mitochondrial inner membrane that is clearly distinguishable from the classical PT and releases apoptogenic cytochrome c in a classical PT-independent manner.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of Tokushima, Shomachi 1, Tokushima 770-8505. radwanjp@yahoo.com
authors.forename: Mohamad Radwan
authors.initials: MR
authors.lastname: Almofti
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Kikuji
authors.initials: K
authors.lastname: Yamashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Shinohara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000737:chemistry / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D019069:Cell Respiration / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D007477:Ions / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012834:Silver / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007477:Ions; D024101:Mitochondrial Proteins; D012834:Silver; D011092:Polyethylene Glycols; D016572:Cyclosporine; D045304:Cytochromes c; D002118:Calcium