The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by sustained immune activation and profound metabolic dysregulation. Accumulating evidence indicates that mitochondrial DNA (mtDNA) plays an active role in linking mitochondrial stress to innate immune signaling in RA. This review synthesizes current findings within a unifying mechanistic framework centered on the mtDNA damage-release-immune activation axis. Owing to limited chromatin protection and constrained repair capacity, mtDNA is highly susceptible to oxidative injury in the inflammatory microenvironment of RA, leading to copy number alterations and mutational accumulation. Damaged or oxidized mtDNA can translocate to the cytosol or extracellular space, where it acts as an immunostimulatory danger signal and amplifies innate immune activation. Persistent mtDNA-related signaling, together with oxidative stress and impaired mitochondrial quality control, contributes to immunometabolic reprogramming in key effector populations. Clinically, circulating cell-free mitochondrial DNA has emerged as a dynamic biomarker associated with disease activity and therapeutic response. Collectively, this framework integrates mitochondrial dysfunction with immune activation in RA and highlights mtDNA-centered pathways as rational targets for mechanism-based intervention. Further standardization of mtDNA assays and mechanism-informed clinical studies will be essential to advance mtDNA-focused precision strategies in RA.