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Mol. Cell. Biol. 20 (10): 3590-3596

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, May 2000, p. 3590-3596, Vol. 20, No. 10
Copyright © 2000, American Society for Microbiology. All rights reserved.

Role of Oxidative Phosphorylation in Bax Toxicity

Marian H. Harris,1 Matthew G. Vander Heiden,2 Stephen J. Kron,3 and Craig B. Thompson1,*

Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 and Committee on Immunology2 and Department of Molecular Genetics and Cell Biology,3 University of Chicago, Chicago, Illinois 60637

Received 21 October 1999/Returned for modification 1 December 1999/Accepted 11 February 2000

The Bcl-2-related protein Bax is toxic when expressed either in yeast or in mammalian cells. Although the mechanism of this toxicity is unknown, it appears to be similar in both cell types and dependent on the localization of Bax to the outer mitochondrial membrane. To investigate the role of mitochondrial respiration in Bax-mediated toxicity, a series of yeast mutant strains was created, each carrying a disruption in either a component of the mitochondrial electron transport chain, a component of the mitochondrial ATP synthesis machinery, or a protein involved in mitochondrial adenine nucleotide exchange. Bax toxicity was reduced in strains lacking the ability to perform oxidative phosphorylation. In contrast, a respiratory-competent strain that lacked the outer mitochondrial membrane Por1 protein showed increased sensitivity to Bax expression. Deficiencies in other mitochondrial proteins did not affect Bax toxicity as long as the ability to perform oxidative phosphorylation was maintained. Characterization of Bax-induced toxicity in wild-type yeast demonstrated a growth inhibition that preceded cell death. This growth inhibition was associated with a decreased ability to carry out oxidative phosphorylation following Bax induction. Furthermore, cells recovered following Bax-induced growth arrest were enriched for a petite phenotype and were no longer able to grow on a nonfermentable carbon source. These results suggest that Bax expression leads to an impairment of mitochondrial respiration, inducing toxicity in cells dependent on oxidative phosphorylation for survival. Furthermore, Bax toxicity is enhanced in yeast deficient in the ability to exchange metabolites across the outer mitochondrial membrane.

* 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}

Molecular and Cellular Biology, May 2000, p. 3590-3596, Vol. 20, No. 10
Copyright © 2000, American Society for Microbiology. All rights reserved.

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