Circulating Cell-Free Mitochondrial DNA as a Novel Biomarker for Tissue Damage, Oxidative Stress, and Systemic Inflammation

Circulating cell-free mitochondrial DNA (cf-mtDNA) has emerged as a promising biomarker for tissue damage, oxidative stress, and systemic inflammation. Unlike nuclear DNA, cf-mtDNA is released into the bloodstream in response to cellular stress, mitochondrial dysfunction, and necrosis, making it a sensitive indicator of pathological processes. This review explores the biological mechanisms of cf-mtDNA release, its role in activating innate immune responses (e.g., via TLR9 and cGAS-STING pathways), and its clinical utility across diverse conditions, including trauma, sepsis, neurodegenerative diseases, and cardiovascular disorders. We highlight advances in detection technologies, such as digital PCR and next-generation sequencing, and discuss challenges in standardization and interpretation. The potential of cf-mtDNA as a dynamic, real-time biomarker for monitoring disease progression and therapeutic response is underscored, alongside future directions in multi-modal biomarker integration and point-of-care applications.