UVA irradiation promotes ROS-mediated formation of the common deletion in mitochondrial DNA

Ultraviolet (UV) radiation from the sun causes adverse skin changes such as premature aging. UV-induced mitochondrial DNA (mtDNA) alterations, including deletions, contribute to photoaging and cellular dysfunction. The most frequent mtDNA rearrangement is the common deletion (CD), characterized by the loss of nearly one-third of the genome (4,977 bp). Although UV radiation exposure leads to CD formation, the molecular mechanisms initiating UV-induced CD remain poorly defined. In this study, we show that increasing UV doses increase CD levels in human skin fibroblasts. UVA exposure increased cellular reactive oxygen species (ROS) and mtDNA oxidation. Antioxidant preconditioning prevented UVA-induced CD accumulation, indicating a ROS-dependent mechanism. Conversely, UVB exposure induced cyclobutane pyrimidine dimers (CPDs) without affecting ROS, suggesting a ROS-independent pathway. Using a 3D full-thickness human skin model, we confirmed UVA-dependent CD formation in both epidermis and dermis. RNA-Seq analysis of UVA-exposed fibroblasts revealed upregulation of mitochondrial DNA replication genes and downregulation of mtDNA repair genes. Taken together, our findings provide insight into how UVA and UVB differ in their detrimental effects on mtDNA, with UVA impacting mtDNA maintenance and transcription via a ROS-dependent mechanism.