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Molecular and Cellular Biology, June 2002, p. 4086-4093, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4086-4093.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mitochondrial Dysfunction Due to Oxidative Mitochondrial DNA Damage Is Reduced through Cooperative Actions of Diverse Proteins

Thomas W. O'Rourke,1 Nicole A. Doudican,1,2 Melinda D. Mackereth,1,2 Paul W. Doetsch,1,3 and Gerald S. Shadel1*

Department of Biochemistry, Emory University School of Medicine, Rollins Research Center,1 Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine,3 Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, Georgia 303222

Received 7 December 2001/ Returned for modification 6 February 2002/ Accepted 18 March 2002

The mitochondrial genome is a significant target of exogenous and endogenous genotoxic agents; however, the determinants that govern this susceptibility and the pathways available to resist mitochondrial DNA (mtDNA) damage are not well characterized. Here we report that oxidative mtDNA damage is elevated in strains lacking Ntg1p, providing the first direct functional evidence that this mitochondrion-localized, base excision repair enzyme functions to protect mtDNA. However, ntg1 null strains did not exhibit a mitochondrial respiration-deficient (petite) phenotype, suggesting that mtDNA damage is negotiated by the cooperative actions of multiple damage resistance pathways. Null mutations in ABF2 or PIF1, two genes implicated in mtDNA maintenance and recombination, exhibit a synthetic-petite phenotype in combination with ntg1 null mutations that is accompanied by enhanced mtDNA point mutagenesis in the corresponding double-mutant strains. This phenotype was partially rescued by malonic acid, indicating that reactive oxygen species generated by the electron transport chain contribute to mitochondrial dysfunction in abf2{Delta} strains. In contrast, when two other genes involved in mtDNA recombination, CCE1 and NUC1, were inactivated a strong synthetic-petite phenotype was not observed, suggesting that the effects mediated by Abf2p and Pif1p are due to novel activities of these proteins other than recombination. These results document the existence of recombination-independent mechanisms in addition to base excision repair to cope with oxidative mtDNA damage in Saccharomyces cerevisiae. Such systems are likely relevant to those operating in human cells where mtDNA recombination is less prevalent, validating yeast as a model system in which to study these important issues.

* Corresponding author. Mailing address: Department of Biochemistry, Emory University School of Medicine, Rollins Research Center, Atlanta, GA 30322. Phone: (404) 727-3798. Fax: (404) 727-3954. E-mail: gshadel{at}emory.edu.

Molecular and Cellular Biology, June 2002, p. 4086-4093, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4086-4093.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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