Mitochondrial dysfunction in asthma: damage signals sustain airway inflammation and remodeling

Asthma is a heterogeneous disease characterized by chronic airway inflammation and airway remodeling. Growing evidence suggests that mitochondrial dysfunction is not only a consequence of inflammatory injury but may also contribute to disease persistence and progression. In asthma, mitochondrial redox balance, energy metabolism, Ca 2+ homeostasis, dynamics, biogenesis, and quality control can all become dysregulated. These abnormalities are interconnected and can alter mitochondrial energy supply, structural integrity, and quality maintenance. Mitochondrial damage can increase mitochondrial reactive oxygen species, promote the mislocalization of mitochondrial nucleic acids, alter membrane lipid oxidation and remodeling, and induce the release of mitochondrial proteins and other components. These changes generate diverse mitochondria-derived damage signals that can regulate inflammation-related gene transcription, nucleic acid sensing, and inflammasome activation. More broadly, mitochondrial abnormalities also alter immune cell function, airway epithelial repair, smooth muscle cell accumulation, and extracellular matrix production. Together, these effects may contribute to persistent airway inflammation and airway remodeling. This review summarizes the major forms of mitochondrial dysfunction in asthma. It also examines how these abnormalities generate mitochondria-derived damage signals, engage inflammatory sensing, and alter immune and airway structural cell functions.