Pulmonary arterial hypertension (PAH) is recognized as a mitochondria-centered disease characterized by early bioenergetic and redox abnormalities that influence pulmonary vascular remodeling. Oxidized mitochondrial DNA (Ox-mtDNA), which combines mitochondrial stress with innate immune activation and dysregulated Ca2+ signaling to sustain hyperproliferation and apoptosis resistance in pulmonary arterial endothelial and smooth muscle cells, is a persistent danger signal rather than just a result of mitochondrial injury. Vasodilator therapy targeting the prostacyclin, nitric oxide, and endothelin pathways has made great strides, yet many patients still make progress. These treatments primarily enhance hemodynamics and vasomotor tone, but they do not directly reverse the cellular and molecular mechanisms that sustain pulmonary vascular remodeling. In this model, inflammatory signaling and mitochondrial redox imbalance are mutually reinforcing rather than strictly sequential: oxidative stress produces Ox-mtDNA, which mediates inflammatory activation, and cytokine and interferon signaling from the inflammatory process further weakens antioxidant defenses and mitochondrial respiration, increasing reactive oxygen species (ROS) output. Because Ox-mtDNA's synthesis, escape, sensing, and clearance all influence inflammatory tone and Ca2+ homeostasis, convergent experimental and clinical observations support Ox-mtDNA as an upstream, therapeutically actionable node. This review describes how mtDNA oxidation, reactive oxygen species amplification, and mitochondrial Ca2+ overload are all facilitated by the convergence of chronic hypoxia, inflammatory cytokines, altered shear stress, and genetic vulnerability. According to the literature, oxidative lesions increase mtDNA bioactivity and persistence when nuclease and autophagy-lysosome clearance systems are overloaded. Pathways of cytosolic and extracellular mtDNA escape, such as vesicular export, mitochondrial permeability transition pore (mPTP) or voltage-dependent anion channel (VDAC)-dependent leakage, and sublethal membrane permeabilization, are summarized in this review. It is also explained how Ox-mtDNA rewires the autophagy-mitophagy axis through reduced flux and skewed signaling, allowing injured mitochondria to continue acting as signal emitters. ER Ca2+ handling and stress-induced remodeling of ER-mitochondria contact sites (MAMs) as upstream amplifiers of mitochondrial damage are also covered. Instead of using prospective, longitudinal cohorts, the majority of these mechanistic data and the correlation between circulating Ox-mtDNA and PAH severity are now based on cross-sectional human sampling and non-PAH disease models. Therefore, until such validation is completed, the biomarker potential of Ox-mtDNA should be considered hypothesis-generating.
