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Molecular and Cellular Biology, August 2000, p. 5680-5689, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Bcl-xL Prevents the Initial Decrease in Mitochondrial Membrane Potential and Subsequent Reactive Oxygen Species Production during Tumor Necrosis Factor Alpha-Induced Apoptosis

Eyal Gottlieb, Matthew G. Vander Heiden, and Craig B. Thompson*

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 9 February 2000/Returned for modification 4 April 2000/Accepted 6 May 2000

The Bcl-2 family of proteins are involved in regulating the redox state of cells. However, the mode of action of Bcl-2 proteins remains unclear. This work analyzed the effects of Bcl-xL on the cellular redox state after treatment with tumor necrosis factor alpha (TNF-alpha ) or exogenous oxidants. We show that in cells that undergo TNF-alpha -induced apoptosis, TNF-alpha induces a partial decrease in mitochondrial membrane potential (Delta Psi m) followed by high levels of reactive oxygen species (ROS). ROS scavengers delay the progression of mitochondrial depolarization and apoptotic cell death. This indicates that ROS are important mediators of mitochondrial depolarization. However, ROS scavengers fail to prevent the initial TNF-alpha -induced decrease in Delta Psi m. In contrast, expression of Bcl-xL prevents both the initial decrease in Delta Psi m following TNF-alpha treatment and the subsequent induction of ROS. Bcl-xL itself does not act as a ROS scavenger. In addition, Bcl-xL does not block the initial decrease in Delta Psi m following treatment with the oxidant hydrogen peroxide. However, unlike control-transfected cells, Bcl-xL-expressing cells can recover their mitochondrial membrane potential following the initial drop in Delta Psi m induced by hydrogen peroxide. These data suggest that Bcl-xL plays a regulatory role in controlling the membrane potential of and ROS production by mitochondria rather than acting as a direct antioxidant.

* Corresponding author. Mailing address: Abramson Family Cancer Research Institute, University of Pennsylvania, 421 Curie Blvd. BRB II/III Rm. 450, Philadelphia, PA 19104-6160. Phone: (215) 746-5515. Fax: (215) 746-5511. E-mail: craig{at}mail.med.upenn.edu.

Molecular and Cellular Biology, August 2000, p. 5680-5689, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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