Deoletion of brain glutathione is accompanied by impaired micochondrial 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.

1H and 31P spectroscopy and bioenergetics in the lateralization of seizures in temporal lobe epilepsy

“…Specifically, the synthesis of NAA is localized to neuronal mitochondria (46). Clarke and his colleagues have demonstrated that in isolated neuronal mitochondria exposed to various oxidative inhibitors, NAA levels decrease and the rates of NAA and ATP synthesis are positively correlated (47,48). Thus the decreased NAA levels seen in epileptics may in fact represent alterations in the function of neuronal mitochondria and their role in modulating seizure activity.…”

Energy Thresholds in Brain Mitochondria

“…GSH is an antioxidant which protects mitochondria from lipid peroxidation (51) and when depleted may render complex I susceptible to free radical attack. Previously, depletion of GSH has been shown to cause enlargement and degeneration of brain mitochondria (52) and a decrease in complex IV activity in purified brain mitochondrial preparations (53). GSH also plays a role in protection of sympathetic neurons in vivo from the effects of the neurotoxin, 1-methyl-4-phenylpyridinium (54) and when mesencephalic cultures are treated with L-BSO, toxicity is potentiated upon exposure to the succinate dehydrogenase inhibitor, malonate (55).…”

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

“…L-NAC is a pluripotent protector that elevates the level of intracellular glutathione, prevents against apoptotic death of neuronal cells, and enhances trophic factor-mediated cell survival (Mayer and Noble, 1994;Ferrari et al, 1995). Indeed, depletion of brain GSH with BSO in rats is accompanied by impaired mitochondrial function and decreased complex IV activity (Heales et al, 1995) leading to energy crisis as a mechanism of nigral cell death (Jenner, 1993).…”