Inhibition of cystathionine-γ-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS

Diwakar, Latha ; Ravindranath, Vijayalakshmi (2007) Inhibition of cystathionine-γ-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS Neurochemistry International, 50 (2). pp. 418-426. ISSN 0197-0186

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Official URL: http://linkinghub.elsevier.com/retrieve/pii/s0197-...

Related URL: http://dx.doi.org/10.1016/j.neuint.2006.09.014

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 (γ-glutamylcysteinyl glycine), an endogenous thiol antioxidant are required for the maintenance of the redox status of cells. Cystathionine γ-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 γ-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 γ-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-β-oxalyl amino-L-alanine, which is the causative factor of a type of motor neuron disease, neurolathyrism. L-β-oxalyl amino-L-alanine toxicity was exacerbated by L-propargylglycine measured as loss of complex I activity indicating the importance of cystathionine γ-lyase in maintaining glutathione levels and in turn the mitochondrial function during excitotoxicity. Oxidative stress generated by L-β-oxalyl amino-L-alanine itself inhibited cystathionine γ-lyase, which could be prevented by prior treatment with thiol antioxidant. Thus, cystathionine γ-lyase itself is susceptible to inactivation by oxidative stress and this can potentially exacerbate oxidant-induced damage. Cystathionine γ-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.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
Keywords:Glutathione; Cystathionine Gamma Lyase; Mitochondrial Dysfunction; Neurodegeneration
ID Code:40635
Deposited On:24 May 2011 14:03
Last Modified:17 May 2016 22:39

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