SIRT3 deficiency drives alveolar epithelial mitochondrial dysfunction in bronchopulmonary dysplasia via PDHA1...

Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in extremely preterm infants, characterized by arrested alveolarization and pulmonary vascular impairment. In neonatal mice and A549 cells, hyperoxia exposure significantly downregulated SIRT3 expression and PDH activity, resulting in severe mitochondrial structural and functional damage. Quantitative acetylome analysis revealed this deficiency leads to the hyperacetylation of PDHA1 at lysine 83. This modification inhibits PDH activity, forcing a pathogenic metabolic shift toward lactate accumulation and mitochondrial dysfunction. In vitro, a deacetylation-mimetic PDHA1-K83R mutant restored PDH activity and mitigated hyperoxia-induced mitochondrial injury. In vivo, pharmacological activation of SIRT3 with Honokiol prevented PDHA1 hyperacetylation, preserved mitochondrial function, and alleviated alveolar simplification. PDHA1 hyperacetylation at K83 is an important downstream event associated with SIRT3 deficiency and contributes to mitochondrial and metabolic dysfunction in hyperoxia-induced BPD. Targeting the SIRT3/PDHA1 axis provides a promising metabolic intervention strategy for BPD treatment.