Double-edged mitophagy: balancing inflammation and resolution in lung disease

Inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and asthma, are driven by mitochondrial dysfunction and aberrant immune responses, yet the regulatory role of mitophagy—a selective autophagy eliminating damaged mitochondria—remains poorly defined. This review synthesizes evidence from in vivo and in vitro studies to dissect the molecular interplay between mitophagy and inflammation. Key fundings reveal that mitophagy exerts context-dependent effects: Protective mitophagy (via PTEN-induced putative kinase 1 [PINK1]-Parkin or FUN14 domain-containing protein 1 [FUNDC1] pathways) clears mitochondrial reactive oxygen species (mtROS)/mitochondrial DNA (mtDNA), suppressing NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and pyroptosis, but excessive mitophagy exacerbates mitochondrial fragmentation and necroptosis. Notably, bidirectional cross-talk exists, and therapeutic strategies—genetic and pharmacological—could restore mitophagy flux, attenuating inflammation in preclinical models. However, challenges persist in targeting tissue-specific mitophagy (such as alveolar and bronchial epithelia). This work underscores mitophagy as a double-edged sword in lung inflammation and proposes precision interventions to balance mitochondrial quality control, offering novel avenues for inflammatory lung diseases.