Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.

Cardiovascular diseases hinge on a vicious, self-amplifying cycle in which mitochondrial deoxyribonucleic acid (mtDNA) dysfunction undermines cardiac bioenergetics and unleashes sterile inflammation. The heart's reliance on oxidative phosphorylation (OXPHOS) makes it exquisitely sensitive to mtDNA insults-mutations, oxidative lesions, copy-number shifts, or aberrant methylation-that impair ATP production, elevate reactive oxygen species (ROS), and further damage the mitochondrial genome. Damaged mtDNA fragments then escape into the cytosol, where they aberrantly engage cGAS-STING, TLR9, and NLRP3 pathways, driving cytokine storms, pyroptosis, and tissue injury. We propose that this cycle represents an almost unifying pathogenic mechanism in a spectrum of mtDNA-driven cardiovascular disorders. In this review, we aim to synthesize the pathophysiological roles of mtDNA in this cycle and its implications for cardiovascular diseases. Furthermore, we seek to evaluate preclinical and clinical strategies aimed at interrupting this cycle-bolstering mtDNA repair and copy-number maintenance, reversing pathogenic methylation, and blocking mtDNA-triggered innate immune activation-and discuss critical gaps that must be bridged to translate these approaches into precision mitochondrial genome medicine for cardiovascular disease.