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Originally published In Press as doi:10.1074/jbc.M007338200 on September 8, 2000

J. Biol. Chem., Vol. 275, Issue 48, 37347-37356, December 1, 2000
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Multiple Signals from Dysfunctional Mitochondria Activate the Pleiotropic Drug Resistance Pathway in Saccharomyces cerevisiae*

Timothy C. Hallstrom and W. Scott Moye-RowleyDagger

From the Molecular Biology Program and the Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

Multiple or pleiotropic drug resistance most often occurs in Saccharomyces cerevisiae due to substitution mutations within the Cys6-Zn(II) transcription factors Pdr1p and Pdr3p. These dominant transcriptional regulatory proteins cause elevated drug resistance and overexpression of the ATP-binding cassette transporter-encoding gene, PDR5. We have carried out a genetic screen to identify negative regulators of PDR5 expression and found that loss of the mitochondrial genome (rho o cells) causes up-regulation of Pdr3p but not Pdr1p function. Additionally, loss of the mitochondrial inner membrane protein Oxa1p generates a signal that results in increased Pdr3p activity. Both of these mitochondrial defects lead to increased expression of the PDR3 structural gene. Importantly, the signaling pathway used to enhance Pdr3p function in rho o cells is not the same as in oxa1 cells. Loss of previously described nuclear-mitochondrial signaling genes like RTG1 reduce the level of PDR5 expression and drug resistance seen in rho o cells but has no effect on oxa1-induced phenotypes. These data uncover a new regulatory pathway connecting expression of multidrug resistance genes with mitochondrial function.

* This work was supported by National Institutes of Health Grant GM49825 (to W. S. M.) and an Established Investigator Award from the American Heart Association (to W. S. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. E-mail: moyerowl@blue.weeg.uiowa.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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