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Molecular and Cellular Biology, June 2009, p. 3099-3112, Vol. 29, No. 11
0270-7306/09/$08.00+0 doi:10.1128/MCB.01845-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Execution of Superoxide-Induced Cell Death by the Proapoptotic Bcl-2-Related Proteins Bid and Bak
,
Muniswamy Madesh,1,¶*
Wei-Xing Zong,2,
,¶
Brian J. Hawkins,1
Subbiah Ramasamy,1
Thilagavathi Venkatachalam,1,
Partha Mukhopadhyay,3
Patrick J. Doonan,1
Krishna M. Irrinki,1
Mohanraj Rajesh,3
Pál Pacher,3 and
Craig B. Thompson2*
Department of Biochemistry, Temple University, 627 Kresge Building, 3440 N. Broad Street, Philadelphia, Pennsylvania 19140,1 Abramson Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,2 Section on Oxidative Stress Tissue Injury, Laboratories of Physiological Studies, National Institutes of Health/NIAAA, Bethesda, Maryland 208923
Received 3 December 2008/ Returned for modification 6 January 2009/ Accepted 19 March 2009
Ethanol intoxication stimulates the production of proinflammatory cytokines, increases the formation of reactive oxygen species, and induces mitochondrial impairment. However, information is limited as to the exact sequence and components involved in ethanol-induced hepatotoxicity. Acute ethanol exposure enhances mitochondrial superoxide (O2.–) production and impairs mitochondrial Ca2+ handling. In turn, O2.– facilitates cytochrome c release and mitochondrial membrane potential loss that is not dependent upon H2O2 and divalent cations and requires Bak in a Bax-independent fashion. Furthermore, triggering of Bak's proapoptotic activity requires the cytosolic presence of Bid, a BH3-only protein that is processed by the initiator caspase-2. Together, these studies identify an O2.–-driven, caspase-initiated apoptotic pathway that selectively involves the Bcl-2 family proteins Bid and Bak. This pathway manifests itself during chronic ethanol consumption in aged animals and identifies caspase-2, Bid, and Bak as essential mediators of O2.–-induced apoptosis that may prove effective targets for the development of therapeutics to treat alcoholic liver disease.
* Corresponding author. Mailing address for Muniswamy Madesh: Department of Biochemistry, Temple University, 627 Kresge Building, 3440 N. Broad Street, Philadelphia, PA 19140. Phone: (215) 707-5465. Fax: (215) 707-7536. E-mail: madeshm{at}temple.edu. Mailing address for Craig B. Thompson: Abramson Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104. Phone: (215) 662-3929. Fax: (215) 662-4020. E-mail: craig{at}mail.med.upenn.edu
Published ahead of print on 30 March 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
¶ These authors contributed equally to this work.
Present address: Department of Molecular Genetics & Microbiology, SUNY—Stony Brook, Stony Brook, NY 11794.
Present address: Department of Medicine, Cooper University Hospital, Camden, NJ 08103.
Molecular and Cellular Biology, June 2009, p. 3099-3112, Vol. 29, No. 11
0270-7306/09/$08.00+0 doi:10.1128/MCB.01845-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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