PMID:10212301

Citation	Fujimura, M, Morita-Fujimura, Y, Kawase, M, Copin, JC, Calagui, B, Epstein, CJ and Chan, PH (1999) Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J. Neurosci. 19:3414-22
Abstract	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 -/+ mice compared with wild-type animals (p < 0.05). N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone (z-VAD.FMK), a nonselective caspase inhibitor, did not affect cytochrome c release after ischemia. A significant amount of DNA laddering was detected 24 hr after ischemia and increased in Sod2 -/+ mice. These data suggest that Mn-SOD blocks cytosolic release of cytochrome c and could thereby reduce apoptosis after permanent FCI.
Links	PubMed
Keywords	Amino Acid Chloromethyl Ketones/pharmacology; Animals; Apoptosis; Blood Pressure; Brain/metabolism; Brain Ischemia/genetics; Brain Ischemia/metabolism; Brain Ischemia/physiopathology; Cardiomyopathy, Dilated/genetics; Cerebral Cortex/metabolism; Cerebral Cortex/pathology; Cerebral Infarction/metabolism; Cysteine Proteinase Inhibitors/pharmacology; Cytochrome c Group/metabolism; Cytosol/metabolism; DNA Fragmentation; Heterozygote; Ischemic Attack, Transient/genetics; Ischemic Attack, Transient/metabolism; Ischemic Attack, Transient/physiopathology; Male; Mice; Mice, Knockout; Mitochondria/metabolism; Oxidative Stress; Rats; Superoxide Dismutase/deficiency; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Superoxides/metabolism
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