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

Miki Fujimura, Yuiko Morita-Fujimura, Makoto Kawase, Jean Christophe Copin, Bernard Calagui, Charles J. Epstein, Pak H. Chan

Research output: Contribution to journalArticle

276 Citations (Scopus)

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-valala- 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.

Original languageEnglish
Pages (from-to)3414-3422
Number of pages9
JournalJournal of Neuroscience
Volume19
Issue number9
DOIs
Publication statusPublished - 1999 May 1

Keywords

  • Apoptosis
  • Caspase
  • Cerebral ischemia
  • Cytochrome c
  • Manganese superoxide dismutase
  • Mitochondrial injury
  • Reactive oxygen species

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice'. Together they form a unique fingerprint.

  • Cite this