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Molecular and Cellular Biology, May 2000, p. 3125-3136, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Biochemical and Genetic Analysis of the Mitochondrial Response of Yeast to BAX and BCL-XL

Atan Gross,1,dagger Kirsten Pilcher,2 Elizabeth Blachly-Dyson,2 Emy Basso,2 Jennifer Jockel,1 Michael C. Bassik,1 Stanley J. Korsmeyer,1,* and Michael Forte2,*

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,1 and Vollum Institute, Oregon Health Sciences University, Portland, Oregon 972012

Received 4 November 1999/Returned for modification 7 December 1999/Accepted 2 February 2000

The BCL-2 family includes both proapoptotic (e.g., BAX and BAK) and antiapoptotic (e.g., BCL-2 and BCL-XL) molecules. The cell death-regulating activity of BCL-2 members appears to depend on their ability to modulate mitochondrial function, which may include regulation of the mitochondrial permeability transition pore (PTP). We examined the function of BAX and BCL-XL using genetic and biochemical approaches in budding yeast because studies with yeast suggest that BCL-2 family members act upon highly conserved mitochondrial components. In this study we found that in wild-type yeast, BAX induced hyperpolarization of mitochondria, production of reactive oxygen species, growth arrest, and cell death; however, cytochrome c was not released detectably despite the induction of mitochondrial dysfunction. Coexpression of BCL-XL prevented all BAX-mediated responses. We also assessed the function of BCL-XL and BAX in the same strain of Saccharomyces cerevisiae with deletions of selected mitochondrial proteins that have been implicated in the function of BCL-2 family members. BAX-induced growth arrest was independent of the tested mitochondrial components, including voltage-dependent anion channel (VDAC), the catalytic beta  subunit or the delta  subunit of the F0F1-ATP synthase, mitochondrial cyclophilin, cytochrome c, and proteins encoded by the mitochondrial genome as revealed by [rho0] cells. In contrast, actual cell killing was dependent upon select mitochondrial components including the beta  subunit of ATP synthase and mitochondrial genome-encoded proteins but not VDAC. The BCL-XL protection from either BAX-induced growth arrest or cell killing proved to be independent of mitochondrial components. Thus, BAX induces two cellular processes in yeast which can each be abrogated by BCL-XL: cell arrest, which does not require aspects of mitochondrial biochemistry, and cell killing, which does.

* Corresponding authors. Mailing address for Dr. Forte: Vollum Institute, L474, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201. Phone: (503) 494-5454. Fax: (503) 494-4976. E-mail: forte{at}ohsu.edu. Mailing address for Dr. Korsmeyer: Dana-Farber Cancer Institute, Harvard Medical School, One Jimmy Fund Way, SM-758, Boston, MA 02115. Phone: (617) 632-6402. Fax: (617) 632-6401. E-mail: Stanley_Korsmeyer{at}dfci.harvard.edu.

dagger Present address: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.

Molecular and Cellular Biology, May 2000, p. 3125-3136, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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