title: Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration.
abstract: The effect of depletion of reduced glutathione (GSH) on brain mitochondrial function and N-acetyl aspartate concentration has been investigated. Using pre-weanling rats, GSH was depleted by L-buthionine sulfoximine administration for up to 10 days. In both whole brain homogenates and purified mitochondrial preparations complex IV (cytochrome c oxidase) activity was decreased, by up to 27%, as a result of this treatment. In addition, after 10 days of GSH depletion, citrate synthase activity was significantly reduced, by 18%, in the purified mitochondrial preparations, but not in whole brain homogenates, suggesting increased leakiness of the mitochondrial membrane. The whole brain N-acetyl aspartate concentration was also significantly depleted at this time point, by 11%. It is concluded that brain GSH is important for the maintenance of optimum mitochondrial function and that prolonged depletion leads also to loss of neuronal integrity. The relevance of these findings to Parkinson's disease and the inborn errors of glutathione metabolism are also discussed.
authors.affiliation: Department of Neurochemistry, University of London, England.
authors.forename: S J
authors.initials: SJ
authors.lastname: Heales
authors.forename: S E
authors.initials: SE
authors.lastname: Davies
authors.forename: T E
authors.initials: TE
authors.lastname: Bates
authors.forename: J B
authors.initials: JB
authors.lastname: Clark
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019328:Buthionine Sulfoximine; D005978:Glutathione / Q000172:deficiency*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats
chemical_list: D008717:Methionine Sulfoximine; D001224:Aspartic Acid; D019328:Buthionine Sulfoximine; C000179:N-acetylaspartate; D005978:Glutathione