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

Free Radical Biology & Medicine
Shankar J ChintaJ K Andersen

Abstract

Up-regulation of activity of gamma-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.

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Citations

Oct 5, 2010·Journal of Neural Transmission·Francisco J GómezMarco T Núñez
Jan 5, 2011·The Journal of Biological Chemistry·Steven R DanielsonJulie K Andersen
Jan 18, 2011·Antioxidants & Redox Signaling·Ying XiongDanyelle M Townsend
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Sep 14, 2011·Evidence-based Complementary and Alternative Medicine : ECAM·Zhong-Ji QianWon-Kyo Jung
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Jul 22, 2009·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Yusuke IwasakiHiroyuki Nakazawa
Apr 9, 2008·Free Radical Biology & Medicine·Steven R Danielson, Julie K Andersen
Mar 31, 2007·Toxicology and Applied Pharmacology·Derek A DrechselManisha Patel
Mar 20, 2008·Phytotherapy Research : PTR·Sang Il LeeYong Chool Boo
May 15, 2013·Free Radical Biology & Medicine·Michelle Smeyne, Richard Jay Smeyne
Aug 2, 2008·Free Radical Research·Magdalena L Circu, Tak Yee Aw
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Jan 17, 2020·Critical Reviews in Toxicology·Patrick E Hanna, M W Anders
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Oct 31, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yahya AltınkaynakAsım Örem

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