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Isoform 1 of uracil-DNA glycosylase (UNG1) is the major protein for initiating base-excision repair in mitochondria and is in close proximity to the respiratory chain that generates reactive oxygen species (ROS). Effects of ROS on the stability of UNG1 have not been well characterized. In the present study, we found that overexpression of UNG1 enhanced cells' resistance to oxidative stress and protected mitochondrial DNA (mtDNA) from oxidation. Proteomics analysis showed that UNG1 bound to eight proteins in the mitochondria, including PAPSS2, CD70 antigen, and AGR2 under normal growth conditions, whereas UNG1 mainly bound to Peroxiredoxin 3 (PRDX3) via a disulfide linkage under oxidative stress. We further demonstrated that the UNG1-PRDX3 interaction protected UNG1 from ROS-mediated degradation and prevented mtDNA oxidation. Moreover, our results show that ROS-mediated UNG1 degradation was Lon protease 1 (LonP1)-dependent and mitochondrial UNG1 degradation was aggravated by knockdown of PRDX3 expression. Taken together, these results reveal a novel function of UNG1 in the recruitment of PRDX3 to mtDNA under oxidative stress, enabling protection of UNG1 and UNG1-bound DNA from ROS damage and enhancing cell resistance to oxidative stress.Schematic representation of ROS mediated UNG1 degradation and interactions with PRDX3. UNG1 binds to both DNA and AGR2 under normal growth condition; when cells were treated with H2O2, ROS induced an UNG1-PRDX3 interaction that protects mitochondrial DNA from oxidation and LonP1-dependent UNG1 degradation.Overexpression of UNG1 prevents oxidation of mitochondrial DNA.Mitochondrial UNG1 binds with AGR2 in cells under normal growth conditions.Reactive oxygen species induce UNG1-PRDX3 interaction.Reactive oxygen species mediate LonP1-dependent UNG1 degradation.