Mitophagy in acute lung injury: Recent advances in mechanisms, cell-specific functions, therapeutic implications, and cytopathological relevance

Abstract

Acute lung injury (ALI) and its more severe clinical manifestation, acute respiratory distress syndrome (ARDS), remain major causes of respiratory failure in critically ill patients. The syndrome is characterized by diffuse alveolar damage, uncontrolled inflammation, disruption of the alveolar-capillary barrier, pulmonary edema, and refractory hypoxemia. Although supportive strategies such as lung-protective ventilation, prone positioning, and conservative fluid management have improved outcomes, no specific pharmacological therapy has yet been established. In the past decade, mitochondrial injury has emerged as a central cytopathological event in ALI pathogenesis. Damaged mitochondria produce excessive mitochondrial reactive oxygen species (mtROS), release mitochondrial DNA (mtDNA), and amplify inflammatory signaling, epithelial apoptosis, endothelial permeability, and immune dysregulation. Mitophagy, the selective autophagic removal of dysfunctional mitochondria, is therefore increasingly recognized as a key intracellular quality-control mechanism in the injured lung. This review is based on a systematic literature search of the PubMed, Web of Science, and Scopus databases for publications from January 2015 to 2026. Since 2015, a rapidly expanding body of literature has clarified how mitophagy regulates innate immune activation, metabolic adaptation, cell survival, and tissue repair in ALI. The present review summarizes recent advances in mitophagy-related mechanisms in ALI/ARDS, focusing on the PTEN-induced kinase 1/ Parkin pathway, receptor-mediated mitophagy, mitochondrial dynamics, and lysosomal flux; discusses cell-type-specific roles in alveolar macrophages, alveolar epithelial cells, endothelial cells, and other pulmonary cell populations; examines crosstalk with the NLR family pyrin domain containing 3 inflammasome and cyclic GMP-AMP synthase-stimulator of interferon genes ( cGAS-STING) signaling; and evaluates current therapeutic strategies targeting mitophagy, including AMP-activated protein kinase/sirtuin (SIRT) activation, mTOR modulation, natural products, and mesenchymal stromal cell-based mitochondrial rescue. Finally, unresolved issues, including temporal specificity, biomarker development, and translational validation in human ARDS, are highlighted. Importantly, while the mechanistic and preclinical evidence is compelling, most supporting data derive from cell-based and animal models; clinical therapeutic evidence in patients with ARDS remains limited and requires rigorous validation. Overall, mitophagy has evolved from a descriptive mitochondrial phenomenon into a promising mechanistic and therapeutic framework for ALI. Notably, while the mechanistic framework is well-supported for macrophages, epithelial cells, and endothelial cells, evidence for other cell types (neutrophils, mesenchymal cells) and viral injury contexts remains preliminary and is clearly labeled as such throughout the review.