Mitochondrial DNA in atherosclerosis: Mechanisms, biomarker potential, and therapeutic perspectives

Atherosclerosis is a chronic inflammatory disease in which mitochondrial DNA (mtDNA) has emerged as a key contributor to its pathogenesis. We synthesized evidence from experimental and clinical studies showing that mtDNA damage, release, and mutation profoundly affect endothelial cells, macrophages, and vascular smooth muscle cells, thereby driving plaque initiation and progression. By activating immune signaling pathways-including cGAS-STING, NLRP3 inflammasome, and TLR9-mtDNA amplifies inflammation and oxidative stress, exacerbating atherosclerotic lesion development. We further highlight that mtDNA copy number variations and specific mtDNA mutations may serve as biomarkers for early atherosclerosis detection and risk stratification. In reviewing these data, we also discuss promising therapeutic interventions aimed at mitigating mtDNA damage, such as mitochondria-targeted antioxidants and enhanced mitophagy, which have shown preliminary efficacy in delaying plaque progression. Overall, this review underscores mtDNA's dual role as both a driver of atherosclerosis and a potential diagnostic and therapeutic target.