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Título

Critical role of mitochondrial glutathione in the survival of hepatocytes during hypoxia

AutorLluis, Josep M. ; Morales, Albert ; Blasco, Carmen; Colell Riera, Anna ; Marí, Montserrat ; García-Ruiz, Carmen ; Fernández-Checa, José C.
Palabras claveMitochondria
Oxidative stress
Reactive oxygen species (ROS)
Cell death
Fecha de publicación4-feb-2005
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJournal of Biological Chemistry 280(5): 3224-3232 (2005)
ResumenHypoxia 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.
Versión del editorhttp://dx.doi.org/10.1074/jbc.M408244200
URIhttp://hdl.handle.net/10261/111562
DOI10.1074/jbc.M408244200
Identificadoresdoi: 10.1074/jbc.M408244200
issn: 0021-9258
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