title: γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Neurosciences of Castile and Leon, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Quintana-Cabrera
authors.forename: Seila
authors.initials: S
authors.lastname: Fernandez-Fernandez
authors.forename: Veronica
authors.initials: V
authors.lastname: Bobo-Jimenez
authors.forename: Javier
authors.initials: J
authors.lastname: Escobar
authors.forename: Juan
authors.initials: J
authors.lastname: Sastre
authors.forename: Angeles
authors.initials: A
authors.lastname: Almeida
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolaños
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003067:Coenzymes / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008658:Inactivation, Metabolic; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D003067:Coenzymes; D004151:Dipeptides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013481:Superoxides; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; C017341:gamma-glutamylcysteine; D000094765:Glutathione Peroxidase GPX1