DEPLETION OF BRAIN GLUTATHIONE IS ACCOMPANIED BY IMPAIRED MITOCHONDRIAL-FUNCTION AND DECREASED N-ACETYL ASPARTATE CONCENTRATION

The effect of depletion of reduced glutathione (GSH) on brain mitochon drial function and N-acetyl aspartate concentration has been investiga ted. Using pre-weanling rats, GSH was depleted by L-buthionine sulfoxi mine administration for up to 10 days. In both whole brain homogenates and purified mitochondrial preparations complex IV (cytochrome c oxid ase) activity was decreased, by up to 27%, as a result of this treatme nt. In addition, after 10 days of GSH depletion, citrate synthase acti vity 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 asp artate concentration was also significantly depleted at this time poin t, by 11%. It is concluded that brain GSH is important for the mainten ance of optimum mitochondrial function and that prolonged depletion le ads also to loss of neuronal integrity. The relevance of these finding s to Parkinson's disease and the inborn errors of glutathione metaboli sm are also discussed.