Up-regulation of γ-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson's disease

Abstract

Up-regulation of activity of γ-glutamyl transpeptidase (GGT) has been reported to occur in the Parkinsonian substantia nigra, the area of the brain affected by the disease. Increased GGT activity has been hypothesized to play a role in subsequent mitochondrial complex I (CI) inhibition by increasing cysteine as substrate for cellular uptake. Intracellular cysteine has been proposed to form toxic adducts with dopamine which can be metabolized to compounds which inhibit CI activity. We have demonstrated that in addition to CI inhibition, GGT activity is up-regulated in dopaminergic cells as a consequence of glutathione depletion. Inhibition of GGT rather than resulting in increased CI inhibition results in exacerbation of this inhibitory effect. This suggests that increased GGT activity is likely an adaptive response to the loss of glutathione to conserve intracellular glutathione content and results in a compensatory effect on CI activity rather than in its inhibition as has been previously widely hypothesized.

Evaluation of Markers of Oxidative Stress, Antioxidant Function and Astrocytic Proliferation in the Striatum and Frontal Cortex of Parkinson’s Disease Brains

“…3d-f, g-i). Interestingly, increased activity of c-GT in SN thus contributing to GSH depletion in PD brains has been reported [46,66].…”

Differential effects of quercetin and silymarin on arsenite-induced cytotoxicity in two human breast adenocarcinoma cell lines

“…This phenomenon was not seen in quercetin treated cells, which had a significant rise after the first 2 h of treatment (2.73 fold), but without showing any variation after the medium change. Since GGT expression is regulated by the cytosolic glutathione pool and steroids (Rasmussen et al, 2005;Chinta et al, 2006), we speculated that the increased quercetin-induced activity might generate enough intracellular glutathione to sustain the enzymatic activity level reached during the recovery time. Conversely, although silymarin increased GGT activity 1.76 fold, it did not protect cells from the medium change-related stress.…”

Oxidative and nitrative protein modifications in Parkinson's disease

“…However, given that both GSH and GSSG are decreased in PD, glutathionylation of complex I is unlikely to be the cause of complex I inhibition in the disease. In order to determine the oxidative or nitrative species involved in the observed CI inhibition, we used scavengers specific for various ROS or RNS [88,89]. Data from these studies indicate that following either acute or chronic glutathione depletion, complex I inhibition appears to be dependent on nitric oxide (NO)-related mechanisms.…”