1152-P: Elucidating Protective Mechanisms of Targeting of hOGG1 to Mitochondria on the HFD-Induced Insulin Resistance in Mice Lacking OGG1

Ogg1 (8-oxoguanine DNA glycosylase-1) is a DNA glycosylase mediating the first step in the base excision repair which removes 8-oxoguanine and repairs oxidized nuclear and mitochondrial (mtDNA). Obesity-induced mtDNA damage heightens mitochondrial oxidative stress, which leads to the development of insulin resistance. Thus, it is important to understand molecular mechanisms by which mtDNA damage induces insulin resistance and to develop therapies including preventative and treatment strategies. Previously we found that mitochondrial targeting of human OGG1 (mt-hOGG1) ameliorated high fat diet (HFD)-induced insulin resistance in Ogg1 deficient (KO) mice in both genetic model (KO/TG mice) and via TAT-protein delivery using intraperitoneal injections (Diabetes 68, Suppl 1, 2019). As we previously demonstrated that Ogg1 contributed to HFD-induced insulin resistance via hepatic insulin resistance (Diabetes 67, Suppl 1, 2018), the goal of the current study was to elucidate the underlying mechanisms for the protective effect of mt-hOGG1 delivery specifically in liver. In this study we found that targeting of mt-hOGG1 prevented hepatic mtDNA from oxidative damage in both genetic model (KO/TG) and via TAT-protein delivery (TAT-mt-hOGG1) to KO mice. Furthermore, delivery of mt-hOGG1 via TAT-protein transduction significantly increased copy number of mtDNA and expression of VDAC1, a mitochondrial marker in liver isolated from TAT-mt-hOGG1 compared to the vehicle treated mice. Studies are underway which will explore the mechanisms by which TAT-mt-hOGG1 increased mtDNA copy number, including evaluation of mitophagy and mitochondrial biogenesis. Collectively, our findings suggested that mt-hOGG1 is critical to preserve mtDNA integrity in liver and provides strong rationale to use TAT-mediated delivery of DNA repair enzymes into mitochondria as a new translational approach for treatment of obesity-induced insulin resistance. Disclosure L. Yuzefovych: None. V. M. Pastukh: None. L. Rachek: None.