Lack of the DNA glycosylases MYH and OGG1 in the cancer prone double mutant mouse does not increase mitochondrial DNA mutagenesis.
Reactive oxygen species (ROS) are formed as natural byproducts during aerobic metabolism and readily induce premutagenic base lesions in the DNA. The 8-oxoguanine DNA glycosylase (OGG1) and MutY homolog 1 (MYH) synergistically prevent mutagenesis and cancer formation in mice. Their localization in the mitochondria as well as in the nucleus suggests that mutations in mitochondrial DNA (mtDNA) contribute to the carcinogenesis in the myh⁻/⁻/ogg1⁻/⁻ double knockout mouse. In order to test this hypothesis, we analyzed mtDNA mutagenesis and mitochondrial function in young (1month) and adult (6months) wt and myh⁻/⁻/ogg1⁻/⁻ mice. To our surprise, the absence of OGG1 and MYH had no impact on mtDNA mutation rates in these mice, even at the onset of cancer. This indicates that mtDNA mutagenesis is not responsible for the carcinogenesis of myh⁻/⁻/ogg1⁻/⁻ mice. In line with these results, mitochondrial function was unaffected in the cancerous tissues liver and lung, whereas a significant reduction in respiration capacity was observed in brain mitochondria from the adult myh⁻/⁻/ogg1⁻/⁻ mouse. The reduced respiration capacity correlated with a specific reduction (-25%) in complex I biochemical activity in brain mitochondria. Our results demonstrate that mtDNA mutations are not associated with cancer development in myh⁻/⁻/ogg1⁻/⁻ mice, and that impairment of mitochondrial function in brain could be linked to nuclear DNA mutations in this strain. OGG1 and MYH appear to be dispensable for antimutator function in mitochondria.
Department of Medical Biochemistry, University of Oslo and Oslo University Hospital, Norway.
Ruth
R
Halsne
Ying
Y
Esbensen
Wei
W
Wang
Katja
K
Scheffler
Rajikala
R
Suganthan
Magnar
M
Bjørås
Lars
L
Eide
D000818:Animals; D019069:Cell Respiration / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000172:deficiency* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics
D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase