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J. Biol. Chem., Vol. 280, Issue 5, 3224-3232, February 4, 2005

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Critical Role of Mitochondrial Glutathione in the Survival of Hepatocytes during Hypoxia^*

Josep M. Lluis, Albert Morales, Carmen Blasco, Anna Colell, Montserrat Mari, Carmen Garcia-Ruiz, and José C. Fernandez-Checa¶

From the Liver Unit, Instituto de Malalties Digestives, Hospital Clinic i Provincial, Instituto Investigaciones Biomédicas August Pi i Sunyer and the Department of Experimental Pathology, Instituto Investigaciones Biomédicas, Consejo Superior Investigaciones Cientificas, 08036 Barcelona, Spain

Hypoxia 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 N-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.

Received for publication, July 21, 2004 , and in revised form, November 12, 2004.

^* This 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. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Liver Unit, Hospital Clinic i Provincial, C/Villarroel, 170, 08036 Barcelona, Spain. Fax: 34-93-451-5272; E-mail: checa229{at}yahoo.com.

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