Glutathione mitochondrial

Sathishkumar, K. Gao, X. Raghavamenon, A. C. Murthy, S. N. Kadowitz, P. J. Uppu, R. M. Determination of glutathione, mitochondrial transmembrane potential, and cytotoxicity in H9c2 cardiomyoblasts exposed to reactive oxygen and nitrogen species. Methods Mol. Biol. 2010, 610, 51-61. 

Lash LH, Xu Y, Elfarra AA, et al. 1995. Glutathione-dependent metabolism of trichloroethylene in isolated liver and kidney cells of rats and its role in mitochondrial and cellular toxicity. Drug Metabolism and Disposition 23 846-853. 

Figure 11.2 Loss of glutathione from isolated rat soleus muscles subjected to either repetitive, electrically stimulated, contractile activity ( a ), treated with the mitochondrial inhibitor 2,4-dinitrophenoi ( ) or untreated ( ). Vaiues significantly different to resting controi muscles, P < 0.05 P < 0.01. Redrawn from Jackson et al. (1991).

Glutathione has specific transporters for its entry into mitochondria (as has iron, see later) such that any defects in its transport into the mitochondria will be important contributing factors in precipitating mitochondrial toxicity. Evidence that dicarboxylate and 2-oxoglutamate may be carriers for glutathione into the mitochondria has recently been published (Chen et at, 2000). 

NADPH is also used to keep the cellular (and mitochondrial) glutathione in the reduced form through the action of glutathione reductase 1... 

Similar to peroxynitrite, ONOOCOO- reacts with many biomolecules such as uric acid [110], oxyhemoglobin [133], melatonin [135], NADH, ubiquinol Q0, and glutathione [141], Reactions of ONOOCOO with substrates in mitochondrial matrix is accompanied by protein nitration [141]. The reaction of ONOOCOO- with GSH was so rapid that glutathione inhibited tyrosine nitration by peroxynitrite in the presence of C02 [142], The formation of ONOOCOO- increased the formation of 3-nitrotyrosine and decreased the formation of 3-hydroxytyrosine probably due to the enhanced selectivity of C03 - compared to hydroxyl radicals [143],... 

As a rule, oxygen radical overproduction in mitochondria is accompanied by peroxidation of mitochondrial lipids, glutathione depletion, and an increase in other parameters of oxidative stress. Thus, the enhancement of superoxide production in bovine heart submitochondrial particles by antimycin resulted in a decrease in the activity of cytochrome c oxidase through the peroxidation of cardiolipin [45]. Iron overload also induced lipid peroxidation and a decrease in mitochondrial membrane potential in rat liver mitochondria [46]. Sensi et al. [47] demonstrated that zinc influx induced mitochondrial superoxide production in postsynaptic neurons. 

O Donnell et al. [70] found that LOX and not cyclooxygenase, cytochrome P-450, NO synthase, NADPH oxidase, xanthine oxidase, ribonucleotide reductase, or mitochondrial respiratory chain is responsible for TNF-a-mediated apoptosis of murine fibrosarcoma cells. 15-LOX activity was found to increase sharply in heart, lung, and vascular tissues of rabbits by hypercholesterolemia [71], Schnurr et al. [72] demonstrated that there is an inverse regulation of 12/15-LOXs and phospholipid hydroperoxide glutathione peroxidases in cells, which balanced the intracellular concentration of oxidized lipids. 

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

SWNTs (10 or 40pg/mouse) Male C57BL/6 mice Single intrapharyngeal instillation 7 days, 28 days, mtDNA damage was accompanied by changes in and 60 days aortic mitochondrial glutathione and protein carbonyl levels Li et al. (2007)... 

Nomura, K., Imai H., Koumura T., Kobayashi, T., andNakagawa, Y., 2000, Mitochondrial phosphohpid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiohpin in hypoglycaemia-induced apoptosis, Biochem. J. 351 183-193. 

Nitric-oxide-induced apoptosis in human leukemic lines requires mitochondrial Upid degradation and cytochrome c lelease. Blood, 93 2342-2352 Wendel, A., 1981, Glutathione peroxidase. Methods Enzymol. 77 325-333... 

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