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

Narrative review synthesizing current understanding of mitochondrial dysfunction and metabolic reprogramming in ARDS

“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.”

Acute respiratory distress syndrome (ARDS) pathophysiology involving alveolar macrophages, neutrophils, alveolar epithelial cells, and pulmonary endothelial cells

“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.”

Mitochondrial dysfunction acts as a central pathogenic hub in ARDS, characterized by excessive ROS production, impaired mitophagy, aberrant dynamics, reduced biogenesis, and mtDNA release, which trigger inflammatory cascades via cGAS/STING and NLRP3 pathways.

“Accumulating evidence has established mitochondrial dysfunction as a central pathogenic hub in ARDS.”

ARDS involves a metabolic shift from oxidative phosphorylation to aerobic glycolysis (Warburg effect), where key glycolytic enzymes reinforce mitochondrial damage through lactate production and HIF-1α stabilization.

“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.”

Mitochondrial and metabolic alterations are cell-type-specific, with alveolar macrophages undergoing pyroptosis, neutrophils promoting NETosis, epithelial cells exhibiting barrier disruption or fibrosis, and endothelial cells showing hyperpermeability due to mitochondrial fission.

“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.”

Challenges include cell specificity, safety concerns regarding off-target effects, and the lack of validated biomarkers for patient stratification, with most evidence derived from preclinical models that may not fully recapitulate human clinical ARDS.

“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.”