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

TitleMitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis.
Publication TypeJournal Article
Year of Publication2012
Authorsvon Montfort, C, Matias, N, Fernandez, A, Fucho, R, de la Rosa, LConde, Martinez-Chantar, MLuz, Mato, JM, Machida, K, Tsukamoto, H, Murphy, MP, Mansouri, A, Kaplowitz, N, Garcia-Ruiz, C, Fernandez-Checa, JC
JournalJ Hepatol
Volume57
Issue4
Pagination852-9
Date Published2012 Oct
ISSN1600-0641
KeywordsAlanine Transaminase, Animals, Antimycin A, Apoptosis, Choline Deficiency, Diet, Disease Models, Animal, Fatty Liver, Free Radical Scavengers, Glutathione, Hepatocytes, Hydrogen Peroxide, Male, Metalloporphyrins, Methionine, Methionine Adenosyltransferase, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mitochondria, Liver, Oxidation-Reduction, Pentanoic Acids, Peroxiredoxin III, Primary Cell Culture, Reactive Oxygen Species, Superoxide Dismutase, Superoxides, Thioredoxins
Abstract

BACKGROUND & AIMS: Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H(2)O(2) by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H(2)O(2) reduction, we explored the interplay between superoxide, H(2)O(2), 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 H(2)O(2) 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.

DOI10.1016/j.jhep.2012.05.024
Alternate JournalJ. Hepatol.
Citation Key10.1016/j.jhep.2012.05.024
PubMed ID22687340
PubMed Central IDPMC3445734
Grant ListP50AA11999 / AA / NIAAA NIH HHS / United States
R01AT1576 / AT / NCCIH NIH HHS / United States
R01 AT001576 / AT / NCCIH NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
R01 AA018857 / AA / NIAAA NIH HHS / United States
R01AA018857 / AA / NIAAA NIH HHS / United States
P50 AA011999 / AA / NIAAA NIH HHS / United States