DRP lyase deficient DNA polymerase beta impairs mitochondrial electron transport chain and compromise mitochondrial DNA integrity

Abstract Endogenous and environmental exposures can induce mitochondrial DNA (mtDNA) damage. Previous studies have shown that mtDNA is particularly vulnerable due to its proximity to mitochondrial reactive oxygen species (ROS) and the absence of histone-like protective proteins, both of which contribute to elevated levels of mtDNA damage. Base excision repair is a critical oxidative DNA damage repair pathway to reverse mitochondria genomic stability. In this work, we examined the impact and repair of ROS-induced DNA damage in the mtDNA due to lose of dRP layse activity of DNA polymerase beta (PolB). We used dRP lyase deficient DNA polymerase beta (PolB-dRP lyase) as a model to uncover the mechanism of mtDNA genomic instability and metabolic dysregulation. We have found that PolB-dRP lyase deficient cells significantly accumulate ROS, decrease mitochondrial encoding antioxidant genes, and low expression of genes involved in electron transport channels (ETC) including respiratory complexes I, II, III and IV. Further PolB-dRP lyase deficient cells exhibit a significant mtDNA damage and replication stress. Moreover, PolB-dRP lyase deficient stomach tissues of mice harbor a significant accumulation of ROS and alter mitochondria signaling pathways. Overall, this work highlights the molecular mechanism associated with PolB-dRP lyase function role in modulating ETC/ROS axis and maintaining mitochondrial DNA integrity.