Mitochondria-Targeted DNA Repair Glycosylase hOGG1 Protects Against HFD-Induced Liver Oxidative Mitochondrial DNA Damage and Insulin Resistance in OGG1-Deficient Mice.

8-oxoguanine DNA glycosylase-1 (OGG1) is a DNA glycosylase mediating the first step in base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mitochondrial DNA. Previous studies showed that OGG1 deficiency results in an increased susceptibility to high-fat diet (HFD)-induced obesity and metabolic dysfunction in mice, suggesting a crucial role of OGG1 in metabolism. However, the tissue-specific mechanisms of how OGG1 deficiency leads to insulin resistance is unknown. Thus, in the current study, we used a hyperinsulinemic-euglycemic clamp to evaluate in-depth glucose metabolism in male wild-type (WT) mice and () mice fed an HFD. mice fed HFD were more obese, with significantly lower hepatic insulin action compared to WT/HFD mice. Targeting human OGG1 to mitochondria protected against HFD-induced obesity, insulin resistance, oxidative mitochondrial DNA damage in the liver and showed decreased expression of liver gluconeogenic genes in mice, suggesting a putative protective mechanism. Additionally, several subunits of oxidative phosphorylation protein levels were noticeably increased in compared to mice fed an HFD which was associated with improved insulin signaling. Our findings demonstrate the crucial role of mitochondrial hOGG1 in HFD-induced insulin resistance and propose several protective mechanisms which can further direct the development of therapeutic treatment.