γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor

Nat Commun. 2012 Mar 6;3:718. doi: 10.1038/ncomms1722.

Abstract

Reactive oxygen species regulate redox-signaling processes, but in excess they can cause cell damage, hence underlying the aetiology of several neurological diseases. Through its ability to down modulate reactive oxygen species, glutathione is considered an essential thiol-antioxidant derivative, yet under certain circumstances it is dispensable for cell growth and redox control. Here we show, by directing the biosynthesis of γ-glutamylcysteine-the immediate glutathione precursor-to mitochondria, that it efficiently detoxifies hydrogen peroxide and superoxide anion, regardless of cellular glutathione concentrations. Knocking down glutathione peroxidase-1 drastically increases superoxide anion in cells synthesizing mitochondrial γ-glutamylcysteine. In vitro, γ-glutamylcysteine is as efficient as glutathione in disposing of hydrogen peroxide by glutathione peroxidase-1. In primary neurons, endogenously synthesized γ-glutamylcysteine fully prevents apoptotic death in several neurotoxic paradigms and, in an in vivo mouse model of neurodegeneration, γ-glutamylcysteine protects against neuronal loss and motor impairment. Thus, γ-glutamylcysteine takes over the antioxidant and neuroprotective functions of glutathione by acting as glutathione peroxidase-1 cofactor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis
  • Cell Line
  • Coenzymes / metabolism
  • Dipeptides / metabolism*
  • Glutathione / metabolism
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism*
  • Glutathione Reductase / genetics
  • Glutathione Reductase / metabolism
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / metabolism
  • Inactivation, Metabolic
  • Mice
  • Mitochondria / metabolism
  • Neurons / metabolism
  • Oxidative Stress / physiology
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism*
  • Superoxides / metabolism

Substances

  • Coenzymes
  • Dipeptides
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Superoxides
  • Hydrogen Peroxide
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Glutathione Reductase
  • Glutathione
  • gamma-glutamylcysteine