title: Inhibition of cystathionine-gamma-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS.
abstract: Oxidative stress has been implicated in the pathogenesis and progression of neurodegenerative disorders and antioxidants potentially have a major role in neuroprotection. Optimum levels of glutathione (gamma-glutamylcysteinyl glycine), an endogenous thiol antioxidant are required for the maintenance of the redox status of cells. Cystathionine gamma-lyase is the rate-limiting enzyme for the synthesis of cysteine from methionine and availability of cysteine is a critical factor in glutathione synthesis. In the present study, we have examined the role of cystathionine gamma-lyase in maintaining the redox homeostasis in brain, particularly with reference to mitochondrial function since the complex I of the electron transport chain is sensitive to redox perturbation. Inhibition of cystathionine gamma-lyase by l-propargylglycine caused loss of glutathione and decrease in complex I activity in the brain although the enzyme activity in mouse brain was 1% of the corresponding hepatic activity. We then examined the effect of this inhibition on the neurotoxicity mediated by the excitatory amino acid, l-beta-oxalyl amino-l-alanine, which is the causative factor of a type of motor neuron disease, neurolathyrism. l-beta-Oxalyl amino-l-alanine toxicity was exacerbated by l-propargylglycine measured as loss of complex I activity indicating the importance of cystathionine gamma-lyase in maintaining glutathione levels and in turn the mitochondrial function during excitotoxicity. Oxidative stress generated by l-beta-oxalyl amino-l-alanine itself inhibited cystathionine gamma-lyase, which could be prevented by prior treatment with thiol antioxidant. Thus, cystathionine gamma-lyase itself is susceptible to inactivation by oxidative stress and this can potentially exacerbate oxidant-induced damage. Cystathionine gamma-lyase is present in neuronal cells in human brain and its activity is several-fold higher compared to mouse brain. It could potentially play an important role in maintaining glutathione and protein thiol homeostasis in brain and hence afford neuroprotection.
authors.affiliation: Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar 122050, Haryana, India.
authors.forename: Latha
authors.initials: L
authors.lastname: Diwakar
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D000328:Adult; D000599:Amino Acids, Diamino / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000502:physiology*; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors*; D004229:Dithiothreitol / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000378:metabolism; D018846:Excitatory Amino Acids / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology
chemical_list: D000599:Amino Acids, Diamino; D018846:Excitatory Amino Acids; C100126:oxalyldiaminopropionic acid; D008063:Thioctic Acid; D003542:Cystathionine gamma-Lyase; D042967:Electron Transport Complex I; D005978:Glutathione; D004229:Dithiothreitol