Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA.

Wauchope OR, Mitchener MM, Beavers WN, Galligan JJ, Camarillo JM, Sanders WD, Kingsley PJ, Shim HN, Blackwell T, Luong T, deCaestecker M, Fessel JP, Marnett LJ
Nucleic Acids Res. 2018 46 (7): 3458-3467

PMID: 29438559 · PMCID: PMC5909422 · DOI:10.1093/nar/gky089

Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.

MeSH Terms (19)

Animals Bone Morphogenetic Protein Receptors, Type II DNA, Mitochondrial DNA Adducts Electron Transport Endothelial Cells Gene Expression Regulation Humans Hypertension, Pulmonary Lipid Peroxidation Mice Mice, Transgenic Mitochondria Mutagenesis Oxidants Oxidative Stress Purine Nucleosides Reactive Oxygen Species Superoxides

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