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J. Biol. Chem., Vol. 282, Issue 40, 29296-29304, October 5, 2007

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Glutathione Binding to the Bcl-2 Homology-3 Domain Groove

A MOLECULAR BASIS FOR BCL-2 ANTIOXIDANT FUNCTION AT MITOCHONDRIA^*

Angela K. Zimmermann, F. Alexandra Loucks, Emily K. Schroeder, Ron J. Bouchard, Kenneth L. Tyler^¶, and Daniel A. Linseman^||**1

From the ^||Eleanor Roosevelt Institute and the Department of Biological Sciences, University of Denver, Denver, Colorado 80208, the Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, the ^**Division of Clinical Pharmacology and Toxicology, the Neuroscience Program, and the ^¶Departments of Neurology, Medicine, and Microbiology & Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Bcl-2 protects cells against mitochondrial oxidative stress and subsequent apoptosis. However, the mechanism underlying the antioxidant function of Bcl-2 is currently unknown. Recently, Bax and several Bcl-2 homology-3 domain (BH3)-only proteins (Bid, Puma, and Noxa) have been shown to induce a pro-oxidant state at mitochondria (1-4). Given the opposing effects of Bcl-2 and Bax/BH3-only proteins on the redox state of mitochondria, we hypothesized that the antioxidant function of Bcl-2 is antagonized by its interaction with the BH3 domains of pro-apoptotic family members. Here, we show that BH3 mimetics that bind to a hydrophobic surface (the BH3 groove) of Bcl-2 induce GSH-sensitive mitochondrial dysfunction and apoptosis in cerebellar granule neurons. BH3 mimetics displace a discrete mitochondrial GSH pool in neurons and suppress GSH transport into isolated rat brain mitochondria. Moreover, BH3 mimetics and the BH3-only protein, Bim, inhibit a novel interaction between Bcl-2 and GSH in vitro. These results suggest that Bcl-2 regulates an essential pool of mitochondrial GSH and that this regulation may depend upon Bcl-2 directly interacting with GSH via the BH3 groove. We conclude that this novel GSH binding property of Bcl-2 likely plays a central role in its antioxidant function at mitochondria.

Received for publication, April 4, 2007 , and in revised form, August 7, 2007.

^* This work was supported by Merit Review Grants from the Dept. of Veterans Affairs (to D. A. L. and K. L. T.) and National Institutes of Health Grants R01 NS050138 and 1R01 NS051403 (to K. L. T.). This work has previously been presented in part at the Society for Neuroscience Annual Meeting in October, 2006. 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.

¹ To whom correspondence should be addressed: Eleanor Roosevelt Institute and Dept. of Biological Sciences, University of Denver, F. W. Olin Hall, Rm. 102, 2190 E. Iliff Ave., Denver, CO 80208. Tel.: 303-871-5654; Fax: 303-871-3471; E-mail: daniel.linseman{at}du.edu.

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