Mitophagy in kidney and lung epithelial cells: molecular mechanisms, crosstalk, and therapeutic interventions

Mitophagy is a central component of mitochondrial quality control in both renal tubular and alveolar epithelial cells, where mitochondrial homeostasis is essential for barrier integrity, energy supply, and stress adaptation. Increasing evidence indicates that mitophagy is highly context-dependent across kidney and lung diseases: insufficient mitochondrial clearance is commonly linked to persistent mitochondrial dysfunction, epithelial senescence, and fibrotic remodeling, whereas dysregulated or excessive mitophagy may aggravate epithelial vulnerability under severe inflammatory or infectious stress. In this review, we summarize the molecular regulation of epithelial mitophagy, including PINK1/Parkin-dependent and receptor-mediated pathways, and examine its divergent roles in acute and chronic injury states in the kidney and lung. We further discuss a proposed mitophagy-centered framework for kidney–lung crosstalk. Current evidence is strongest for kidney-to-lung communication, particularly through circulating mitochondrial damage-associated molecular patterns and inflammatory mediators after acute kidney injury, whereas lung-to-kidney links remain supported mainly by organ-level inflammatory, hypoxemic, and hemodynamic mechanisms rather than direct evidence of pulmonary epithelial mitophagy-driven renal injury. Overall, the available literature supports mitophagy as an important mechanistic interface in epithelial injury, but not yet as a fully validated bidirectional epithelial axis. Future therapeutic strategies should therefore aim to restore mitophagy homeostasis in a disease- and stage-specific manner rather than uniformly enhancing or suppressing mitochondrial clearance.