Human DNA is constantly challenged by both internal and external factors, which leads to a variety of modifications. While some of these modifications are important for genetic regulation, others have mutagenic and pathogenic effects. Our research aims to understand the chemical and molecular mechanisms involved in how the cell handles the modified DNA molecules and exploit chemical approaches to manipulate the relevant biological pathways. We have a particular focus on mitochondrial DNA (mtDNA) maintenance. The mtDNA genome is small and present in multiple copies, and it plays a crucial role in energy production, biosynthesis, and cell signaling. Defects in mtDNA and mtDNA-mediated cell signaling have been linked to a range of mitochondrial diseases, neurodegenerative disorders, and inflammation and aging processes. Our long-term objective is to apply our knowledge to the development of new therapeutic and disease intervention strategies for mitochondria-related disorders.