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Previous Article | Next Article
The Journal of Neuroscience, May 1, 1999, 19(9):3414-3422
Manganese Superoxide Dismutase Mediates the Early Release of Mitochondrial Cytochrome C and Subsequent DNA Fragmentation after Permanent Focal Cerebral Ischemia in Mice
Miki Fujimura1, Yuiko Morita-Fujimura1, Makoto Kawase1, Jean-Christophe Copin1, Bernard Calagui1, Charles J. Epstein2, and Pak H. Chan1 1 Departments of Neurosurgery, Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Palo Alto, California 94304, and 2 Department of Pediatrics, University of California, School of Medicine, San Francisco, California 94143-0748
Recent studies have shown that release of mitochondrial cytochrome c is a critical step in the apoptosis process. We have reported that cytosolic redistribution of cytochrome c in vivo occurred after transient focal cerebral ischemia (FCI) in rats and preceded the peak of DNA fragmentation. Although the involvement of reactive oxygen species in the cytosolic redistribution of cytochrome c in vitro has been suggested, the detailed mechanism by which cytochrome c release is mediated in vivo has not yet been established. Also, the role of mitochondrial oxidative stress in cytochrome c release is unknown. These issues can be addressed using knock-out mutants that are deficient in the level of the mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD). In this study we examined the subcellular distribution of the cytochrome c protein in both wild-type mice and heterozygous knock-outs of the Mn-SOD gene (Sod2
/+) after permanent FCI, in which apoptosis is assumed to participate. Cytosolic cytochrome c was detected as early as 1 hr after ischemia, and correspondingly, mitochondrial cytochrome c showed a significant reduction 2 hr after ischemia (p < 0.01). Cytosolic accumulation of cytochrome c was significantly higher in Sod2
Key words: cerebral ischemia; cytochrome c; manganese superoxide dismutase; apoptosis; mitochondrial injury; reactive oxygen species; caspase
Copyright © 1999 Society for Neuroscience 0270-6474/99/1993414-09$05.00/0
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[Abstract] [Full Text] [PDF]
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