Mitochondrial dysfunction in ARDS: unraveling the regulatory networks and therapeutic opportunities

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality and limited effective pharmacotherapies. Accumulating evidence has established mitochondrial dysfunction as a central pathogenic hub in ARDS. Injured mitochondria exhibit excessive reactive oxygen species production, impaired mitophagy, aberrant dynamics (predominantly Drp1-mediated fission), reduced biogenesis, and release of mitochondrial DNA as a damage-associated molecular pattern. These alterations trigger inflammatory cascades via the cGAS/STING and NLRP3 pathways, while simultaneously driving a metabolic shift from oxidative phosphorylation to aerobic glycolysis, the Warburg effect. Key glycolytic enzymes, including PKM2, PDK4, GAPDH, and PGK1, reinforce mitochondrial damage through lactate production and HIF-1α stabilization, creating a vicious cycle. Notably, PFKFB3 exhibits cell-type-specific duality, exerting protective effects in alveolar epithelial cells while promoting NETosis in neutrophils. Distinct cell types in the lung, alveolar macrophages, neutrophils, alveolar epithelial cells, and pulmonary endothelial cells exhibit unique mitochondrial and metabolic alterations that collectively perpetuate injury and impair repair. Therapeutically, mitochondria-targeted agents (MitoQ, MOTS-c), modulators of mitochondrial dynamics (baicalein, hydrogen), inhibitors of glycolytic enzymes (PFKFB3, PKM2, PDK4), natural compounds (1-octyl itaconate, shikonin, scutellarin), and mesenchymal stromal cell-mediated mitochondrial transfer have shown promise in preclinical models. This review synthesizes current understanding of the regulatory mechanisms linking mitochondrial dysfunction and metabolic reprogramming in ARDS, discusses cell-type-specific contributions, and highlights emerging therapeutic strategies. Targeting mitochondrial homeostasis and the associated glycolytic shift may offer a transformative approach to ARDS treatment, though challenges related to cell specificity, safety, and clinical translation remain.