Mitochondrial DNA (mtDNA) damage heightens mitochondrial oxidative stress, which is very critical for the development of insulin resistance. OGG1 (8-oxoguanine DNA glycosylase-1) is a DNA glycosylase mediating the first step in the base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mtDNA. Previous studies showed that Ogg1 deficiency results in an increased susceptibility to high fat diet (HFD)-induced obesity, metabolic dysfunction and IR in mice, suggesting a crucial role of Ogg1 in glucose metabolism. Here we performed studies in vivo using Ogg1 knockout and overexpressing genetic models: 1)Ogg1 -/- (KO); 2)KO mice with mitochondrial targeted hOGG1 (hOGG1, subunit 1-α; KO/Tg); 3) wild type (WT) mice. Male mice of all three genotypes were fed either high fat diet (HFD) or control low fat diet (LFD) for 16 weeks, and obesity and insulin resistance phenotypes were evaluated. Our results demonstrated that HFD-fed KO mice displayed increased obesity and whole-body insulin resistance phenotype compared to both WT and KO/Tg mice fed with HFD. Additionally, we have utilized a translational strategy of targeting the recombinant hOGG1 into mitochondria using a TAT-protein transduction system. KO mice were fed HFD and vehicle or MTS-hOGG1-TAT protein was administered intraperitoneally twice weekly for 9 weeks. Consistent with results obtained for genetic models, KO mice injected with MTS-hOGG1-TAT showed significantly lower blood glucose levels and insulin resistance phenotype compared to mice injected with vehicle. Our findings suggest that protecting mtDNA from damage might be crucial to prevent insulin resistance. Furthermore, our data provides strong rationale to use TAT-delivery of DNA repair enzymes into mitochondria as a new translational approach for treatment of insulin resistance.
L. Yuzefovych: None. L. Rachek: None.
American Heart Association (16GRNT29150012 to L.R.)