Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis

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Abstract

Background & Aims: Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H2O2 by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H2O2 reduction, we explored the interplay between superoxide, H2O2, and mGSH in nutritional and genetic models of SH, which exhibit mGSH depletion. Methods: We used isolated mitochondria and primary hepatocytes, as well as in vivo SH models showing mGSH depletion to test the consequences of superoxide scavenging. Results: In isolated mitochondria and primary hepatocytes, superoxide scavenging by SOD mimetics or purified SOD decreased superoxide and peroxynitrite generation but increased H2O2 following mGSH depletion, despite mitochondrial peroxiredoxin/thioredoxin defense. Selective mGSH depletion sensitized hepatocytes to cell death induced by SOD mimetics, and this was prevented by RIP1 kinase inhibition with necrostatin-1 or GSH repletion with GSH ethyl ester (GSHee). Mice fed the methionine-choline deficient (MCD) diet or MAT1A-/- mice exhibited reduced SOD2 activity; in vivo treatment with SOD mimetics increased liver damage, inflammation, and fibrosis, despite a decreased superoxide and 3-nitrotyrosine immunoreactivity, effects that were ameliorated by mGSH replenishment with GSHee, but not NAC. As a proof-of-principle of the detrimental role of superoxide scavenging when mGSH was depleted transgenic mice overexpressing SOD2 exhibited enhanced susceptibility to MCD-mediated SH. Conclusions: These findings underscore a critical role for mGSH in the therapeutic potential of superoxide scavenging in SH, and suggest that the combined approach of superoxide scavenging with mGSH replenishment may be important in SH. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Montfort, C. V., Matias, N., Fernandez, A., Fucho, R., De La Rosa, L. C., Martinez-Chantar, M. L., … Fernandez-Checa, J. C. (2012). Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis. Journal of Hepatology, 57(4), 852–859. https://doi.org/10.1016/j.jhep.2012.05.024

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