Elevation of Mitochondrial Glutathione by γ-Glutamylcysteine Ethyl Ester Protects Mitochondria Against Peroxynitrite-Induced Oxidative Stress

Jennifer Drake, Rukhsana Sultana, Marina Aksenova, Vittorio Calabrese, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

Mitochondria under oxidative stress are thought to play a key role in various neurodegenerative disorders by directing neurons to cell death. Protection by antioxidants against oxidative stress to mitochondria may prove to be beneficial in delaying onset or progression of these diseases. We have investigated the ability of γ-glutamylcysteine ethyl ester (GCEE) to upregulate mitochondrial glutathione (GSH) in vivo or in vitro and protect against subsequent in vitro peroxynitrite (ONOO-) damage. Mitochondria pretreated in vitro with GCEE were protected against oxidative damage induced by peroxynitrite, as assessed by mitochondrial swelling, changes in mitochondrial membrane potential, 3-nitrotyrosine formation, protein carbonyl formation, and cytochrome c release. Loss of mitochondrial function in neuronal cell cultures by the oxidants 2,2,′ Azobis(2-amidino-propane)dihydrochloride (AAPH) and ONOO- was ameliorated by treatment with GCEE. In vivo studies showed that mitochondria isolated from animals injected intraperitoneally with GCEE were protected partially against oxidative modifications induced by ONOO-. Taken together, these results suggest that GCEE may be effective in increasing mitochondrial GSH and may be prove to have therapeutic relevance in neurodegenerative disorders associated with oxidative stress and mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)917-927
Number of pages11
JournalJournal of Neuroscience Research
Volume74
Issue number6
DOIs
StatePublished - Dec 15 2003

Keywords

  • Glutathione
  • Mitochondria
  • Oxidative stress
  • Peroxynitrite
  • γ-glutamylcysteine ethyl ester

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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