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Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae.
Mol Cell Biol. 2005 Jun; 25(12):5196-204.MC

Abstract

Mitochondria contain their own genome, the integrity of which is required for normal cellular energy metabolism. Reactive oxygen species (ROS) produced by normal mitochondrial respiration can damage cellular macromolecules, including mitochondrial DNA (mtDNA), and have been implicated in degenerative diseases, cancer, and aging. We developed strategies to elevate mitochondrial oxidative stress by exposure to antimycin and H(2)O(2) or utilizing mutants lacking mitochondrial superoxide dismutase (sod2Delta). Experiments were conducted with strains compromised in mitochondrial base excision repair (ntg1Delta) and oxidative damage resistance (pif1Delta) in order to delineate the relationship between these pathways. We observed enhanced ROS production, resulting in a direct increase in oxidative mtDNA damage and mutagenesis. Repair-deficient mutants exposed to oxidative stress conditions exhibited profound genomic instability. Elimination of Ntg1p and Pif1p resulted in a synergistic corruption of respiratory competency upon exposure to antimycin and H(2)O(2). Mitochondrial genomic integrity was substantially compromised in ntg1Delta pif1Delta sod2Delta strains, since these cells exhibit a total loss of mtDNA. A stable respiration-defective strain, possessing a normal complement of mtDNA damage resistance pathways, exhibited a complete loss of mtDNA upon exposure to antimycin and H(2)O(2). This loss was preventable by Sod2p overexpression. These results provide direct evidence that oxidative mtDNA damage can be a major contributor to mitochondrial genomic instability and demonstrate cooperation of Ntg1p and Pif1p to resist the introduction of lesions into the mitochondrial genome.

Authors+Show Affiliations

Department of Biochemistry, Graduate Program in Genetic and Molecular Biology, Emory University School of Medicine, 4013 Rollins Research Center, Atlanta, GA 30322, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15923634

Citation

Doudican, Nicole A., et al. "Oxidative DNA Damage Causes Mitochondrial Genomic Instability in Saccharomyces Cerevisiae." Molecular and Cellular Biology, vol. 25, no. 12, 2005, pp. 5196-204.
Doudican NA, Song B, Shadel GS, et al. Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae. Mol Cell Biol. 2005;25(12):5196-204.
Doudican, N. A., Song, B., Shadel, G. S., & Doetsch, P. W. (2005). Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae. Molecular and Cellular Biology, 25(12), 5196-204.
Doudican NA, et al. Oxidative DNA Damage Causes Mitochondrial Genomic Instability in Saccharomyces Cerevisiae. Mol Cell Biol. 2005;25(12):5196-204. PubMed PMID: 15923634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae. AU - Doudican,Nicole A, AU - Song,Binwei, AU - Shadel,Gerald S, AU - Doetsch,Paul W, PY - 2005/6/1/pubmed PY - 2005/7/15/medline PY - 2005/6/1/entrez SP - 5196 EP - 204 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 25 IS - 12 N2 - Mitochondria contain their own genome, the integrity of which is required for normal cellular energy metabolism. Reactive oxygen species (ROS) produced by normal mitochondrial respiration can damage cellular macromolecules, including mitochondrial DNA (mtDNA), and have been implicated in degenerative diseases, cancer, and aging. We developed strategies to elevate mitochondrial oxidative stress by exposure to antimycin and H(2)O(2) or utilizing mutants lacking mitochondrial superoxide dismutase (sod2Delta). Experiments were conducted with strains compromised in mitochondrial base excision repair (ntg1Delta) and oxidative damage resistance (pif1Delta) in order to delineate the relationship between these pathways. We observed enhanced ROS production, resulting in a direct increase in oxidative mtDNA damage and mutagenesis. Repair-deficient mutants exposed to oxidative stress conditions exhibited profound genomic instability. Elimination of Ntg1p and Pif1p resulted in a synergistic corruption of respiratory competency upon exposure to antimycin and H(2)O(2). Mitochondrial genomic integrity was substantially compromised in ntg1Delta pif1Delta sod2Delta strains, since these cells exhibit a total loss of mtDNA. A stable respiration-defective strain, possessing a normal complement of mtDNA damage resistance pathways, exhibited a complete loss of mtDNA upon exposure to antimycin and H(2)O(2). This loss was preventable by Sod2p overexpression. These results provide direct evidence that oxidative mtDNA damage can be a major contributor to mitochondrial genomic instability and demonstrate cooperation of Ntg1p and Pif1p to resist the introduction of lesions into the mitochondrial genome. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/15923634/Oxidative_DNA_damage_causes_mitochondrial_genomic_instability_in_Saccharomyces_cerevisiae_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=15923634 DB - PRIME DP - Unbound Medicine ER -