Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice.

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.

• Authors: M Fujimura, Y Morita-Fujimura, M Kawase, J C Copin, B Calagui, C J Epstein, P H Chan
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 19 Issue 9 Pg. 3414-22 (May 01 1999) ISSN: 0270-6474 [Print] United States
• PMID: 10212301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amino Acid Chloromethyl Ketones
• Cysteine Proteinase Inhibitors
• Cytochrome c Group
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Superoxides
• Superoxide Dismutase

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Apoptosis
• Blood Pressure
• Brain (metabolism)
• Brain Ischemia (genetics, metabolism, physiopathology)
• Cardiomyopathy, Dilated (genetics)
• Cerebral Cortex (metabolism, pathology)
• Cerebral Infarction (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• Cytochrome c Group (metabolism)
• Cytosol (metabolism)
• DNA Fragmentation
• Heterozygote
• Ischemic Attack, Transient (genetics, metabolism, physiopathology)
• Male
• Mice
• Mice, Knockout
• Mitochondria (metabolism)
• Oxidative Stress
• Rats
• Superoxide Dismutase (deficiency, genetics, metabolism)
• Superoxides (metabolism)