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dc.contributor.authorLluis, Josep M.-
dc.contributor.authorMorales, Albert-
dc.contributor.authorBlasco, Carmen-
dc.contributor.authorColell Riera, Anna-
dc.contributor.authorMarí, Montserrat-
dc.contributor.authorGarcía-Ruiz, Carmen-
dc.contributor.authorFernández-Checa, José C.-
dc.identifierdoi: 10.1074/jbc.M408244200-
dc.identifierissn: 0021-9258-
dc.identifier.citationJournal of Biological Chemistry 280(5): 3224-3232 (2005)-
dc.description.abstractHypoxia is known to stimulate reactive oxygen species (ROS) generation. Because reduced glutathione (GSH) is compartmentalized in cytosol and mitochondria, we examined the specific role of mitochondrial GSH (mGSH) in the survival of hepatocytes during hypoxia (5% O2). 5% O2 stimulated ROS in HepG2 cells and cultured rat hepatocytes. Mitochondrial complex I and II inhibitors prevented this effect, whereas inhibition of nitric oxide synthesis with Nω-nitro-L-arginine methyl ester hydrochloride or the peroxynitrite scavenger uric acid did not. Depletion of GSH stores in both cytosol and mitochondria enhanced the susceptibility of HepG2 cells or primary rat hepatocytes to 5% O2 exposure. However, this sensitization was abrogated by preventing mitochondrial ROS generation by complex I and II inhibition. Moreover, selective mGSH depletion by (R,S)-3-hydroxy-4-pentenoate that spared cytosol GSH levels sensitized rat hepatocytes to hypoxia because of enhanced ROS generation. GSH restoration by GSH ethyl ester or by blocking mitochondrial electron flow at complex I and II rescued (R,S)-3-hydroxy-4-pentenoate-treated hepatocytes to hypoxia-induced cell death. Thus, mGSH controls the survival of hepatocytes during hypoxia through the regulation of mitochondrial generation of oxidative stress.-
dc.description.sponsorshipThis work was supported in part by the Research Center for Liver and Pancreatic Diseases, P50 AA 11999, and Grant 1R21 AA014135-01 from the National Institute on Alcohol Abuse and Alcoholism, Plan Nacional de I+D grants SAF01-2118, SAF2003-04974, and Red Temática de Investigación Cooperativa G03/015, and Red de Centros C03/02 supported by Instituto de Salud Carlos III-
dc.publisherAmerican Society for Biochemistry and Molecular Biology-
dc.subjectOxidative stress-
dc.subjectReactive oxygen species (ROS)-
dc.subjectCell death-
dc.titleCritical role of mitochondrial glutathione in the survival of hepatocytes during hypoxia-
dc.description.versionPeer Reviewed-
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