The flow of genetic information is critically dependent on the structure and integrity of DNA. DNA is challenged by endogenous and environmental factors, which produces a plethora of DNA modifications. Certain DNA modifications play a role in genetic regulation, whereas others have mutagenic and pathogenic effects. The overarching goal of our research is to understand the chemical and molecular mechanisms by which DNA modifications are dealt with. We are particularly interested in the mitochondrial DNA maintenance. The small and multi-copy mitochondrial DNA genome play a plethora roles in energy production, biosynthesis, and cell signaling. The instability of mtDNA has been associated with a variety of mitochondrial diseases, neurodegeneration, and aging. We use chemical, biochemical, biophysical, computational, and cellular approaches to gain fundamental insights into mtDNA maintenance with a long-term goal to inform the development of novel therapeutics or disease intervention strategies.