Repair of 8-oxodeoxyguanosine lesions in mitochondrial DNA depends on the oxoguanine DNA glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial DNA of OGG1-defective mice

Mitochondria are not only the major site for generation of reactive oxygen species, but also one of the main targets of oxidative damage. One of the m ajor products of DNA oxidation, 8-oxodeoxyguanosine (8-oxodC), accumulates in mitochondrial DNA (mtDNA) at levels three times higher than in nuclear D NA, The main pathway for the repair of 8-oxodG is the base excision repair pathway initiated by oxoguanine DNA glycosylase (OGG1), We previously demon strated that mammalian mitochondria from mice efficiently remove 8-oxodG fr om their genomes and isolated a protein from rat liver mitochondria with 8- oxoguanine (8-oxodG) DNA glycosylase/apurinic DNA lyase activity. In the pr esent study, we demonstrated that the mitochondrial 8-oxodG DNA glycosylase /apurinic DNA lyase activity is the mitochondrial isoform of OGG1, Using mo use liver mitochondria isolated from ogg1(-/-) mice, we showed that the OGG 1 gene encodes for the mitochondrial 8-oxodG glycosylase because these extr acts have no incision activity toward an oligonucleotide containing a singl e 8-oxodG DNA base lesion, Consistent with an important role for the OGG1 p rotein in the removal of 8-oxodC from the mitochondrial genome, we found th at mtDNA isolated from liver from OGG1-null mutant animals contained 20-fol d more 8-oxodC than mtDNA From wild-type animals.