J. Biochem, 2003, Vol. 134, No. 1 43-49
© 2003 Japanese Biochemical Society
BIOCHEMISTRY |
Silver Ion Induces a Cyclosporine A-Insensitive Permeability Transition in Rat Liver Mitochondria and Release of Apoptogenic Cytochrome c
1 Faculty of Pharmaceutical Sciences, The University of Tokushima, Shomachi 1, Tokushima 770-8505; 2 Single-Molecule Bioanalysis Laboratory, National Institute of Advanced Industrial Science and Technology (AIST), Hayashicho, Takamatsu 761-0395; 3 School of Dentistry, The University of Tokushima 4 Institute for Genome Research, The University of Tokushima, Kuramotocho 3-18, Tokushima 770-8503; 5 Faculty of Pharmaceutical Sciences, Tokyo University of Science, Shinjuku-ku, Tokyo 162-0826
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 Ca2+-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.
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