Glutathione deficiency leads to mitochondrial damage in brain.

Abstract

Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of y-glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration ofthe mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex. Some of the oxygen used by mitochondria is known to be converted to hydrogen peroxide. We suggest that in glutathione deficiency, hydrogen peroxide accumulates and damages mitochondria. Glutathione, thus, has an essential function in mitochondria under normal physiological conditions. Observations on turnover and utilization of brain glutathione in newborn, preweaning, and adult rats show that (i) some glutathione turns over rapidly (t ., -30 min in adults, ==8 min in newborns), (ii) several pools of glutathione probably exist, and (iii) brain utilizes plasma glutathione, probably by y-glutamyl transpeptidase-initiated pathways that account for some, but not all, of the turnover; thus, there is recovery or transport of cysteine moieties. These studies provide an animal model for the human diseases involving glutathione deficiency and are relevant to oxidative phenomena that occur in the newborn.Studies in which glutathione (GSH) deficiency was induced in animals by administering L-buthionine (S,R)-sulfoximine (BSO) (1, 2), a transition-state inhibitor of y-glutamylcysteine synthetase (3,4), showed that GSH deficiency leads to myofiber degeneration in skeletal muscle (5), damage to type 2-cell lamellar bodies and capillary endothelial cells in the lung (6), and epithelial-cell damage to jejunum and colon (7) in adult mice, and to lens epithelial-cell degeneration and cataract formation in newborn mice (8, 9) and rats (9). These effects, which were invariably accompanied by markedly decreased mitochondrial GSH levels, were associated with mitochondrial swelling with vacuolization and rupture of cristae and mitochondrial membranes as seen by EM. The isolated mitochondria exhibited decreased citrate synthase activity.It should be emphasized that these effects occurred without application of stress (e.g., increased oxygen, drugs, radiation) and that they were completely prevented by administration of GSH monoesters (10-13). In the absence of evidence that BSO itself exerts a separate type of toxicity other than its effect on the enzyme that catalyzes the first step of GSH synthesis, it may be concluded that a major effect of GSH deficiency is mitochondrial damage. Although mitochondria have long been known to contain GSH, only recently was mitochondrial GSH found to originate from the cytosol and to be imported into mitochondria by a system that contains a high-affinity transporter (14,15). Not all oxygen used by mitochondria is reduced to water, but a significant fraction of it is converted, apparently throu...

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

“…1B). Treatment with 40 μg/ml dox for 24 h resulted in a decrease in GSH levels of approximately 50%, a similar decrease to that previously reported to occur in the SN of early PD brains [2,5]. Consequently, this dosage regime was used for all subsequent experiments.…”

“…GSH is synthesized in the cytosol and transported into the mitochondria via an energy-dependent transporter. Decreased GSH availability in the brain has been demonstrated to promote morphological mitochondrial damage [5]. We have previously demonstrated that GSH depletion via downregulation of GCL activity in dopaminergic cells in vitro results in a rather selective inhibition of CI activity which is rate-limiting with regard to mitochondrial function [6,7].…”

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

“…Glutathione is also essential for maintenance of the thiols of proteins and of other antioxidants, for example, ascorbate and α -tocopherol (18,19). A decreased glutathione level, through inhibition of its synthesis, is accompanied by increased excitotoxic response to NMDA, degeneration of mitochondria, and larger infarct areas in stroke models (20)(21)(22). Extracellularly, glutathione has been suggested to have multifaceted electrophysiological effects by binding to its own receptors and by modulating glutamatergic excitatory neurotransmission by displacing glutamate from its ionotropic receptors (23)(24)(25).…”

Regulation of Neuronal Glutathione Synthesis

“…Brain GSH depletion leads to increased productions of superoxide, hydroxyl radicals, and H 2 O 2 (13). Treatment with Lbuthionine sulfoximine (BSO) a specific inhibitor of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH biosynthesis, leads to GSH depletion (14). Decreased intracellular GSH due to BSO treatment worsened oxidative damage in vivo (15), while increased intracellular GSH due to n-acetylcysteine (NAC) treatment ameliorated this damage (16).…”