The mitochondria-immune axis: A self-amplifying vicious cycle driving the pathogenesis of preeclampsia

Preeclampsia (PE) is a severe pregnancy-specific disorder and a leading cause of maternal and perinatal morbidity and mortality. Although the traditional two-stage model links abnormal placentation to maternal endothelial dysfunction, it does not fully explain how placental stress is converted into persistent systemic inflammation. This review reframes the mitochondria-immune axis as a hierarchical and self-amplifying network in PE. In this model, placental hypoxia-reoxygenation, endoplasmic reticulum stress and anti-angiogenic stress act as initiating events that destabilize mitochondrial homeostasis in trophoblasts, endothelial cells and immune cells. Damaged mitochondria then release reactive oxygen species (ROS), mitochondrial DNA (mtDNA) and other danger signals, which activate innate immune sensors, including the NLRP3 inflammasome, cGAS-STING, TLR9 and NF-kB pathways. These pathways induce IL-1β, TNF-α, type I interferon signaling, complement activation, neutrophil extracellular traps and macrophage/T-cell imbalance, which in turn aggravate mitochondrial injury and sustain a pathogenic feedback loop. We further distinguish the likely contribution of this axis across PE subtypes, including early-onset, late-onset, maternal, canonical and immunological PE. The review critically evaluates circulating mtDNA and mitochondria-related genes as biomarkers, emphasizing the effects of sample processing, vesicle-bound mtDNA, cellular contamination, gestational timing and assay choice. Therapeutic opportunities are discussed according to translational maturity, from clinically relevant supportive approaches and PE-tested preclinical interventions to extrapolated mitochondrial and immunopharmacological strategies. Overall, the mitochondria-immune axis provides a structured framework for subtype-aware biomarker development and mechanism-guided intervention in PE, while highlighting the need for standardized longitudinal cohorts and pregnancy-specific safety validation.