ETS1 targets the SENP2/HSPA8/FUNDC1 axis to ameliorate bronchopulmonary dysplasia by inhibiting mitochondrial damage-induced autophagy.

Mitochondrial damage and subsequent aberrant mitophagy are critical drivers of alveolar simplification in bronchopulmonary dysplasia (BPD). E26 transformation specific-1 (ETS1) is a transcription factor whose role in BPD and its regulation of mitophagy have not been fully investigated. This study aims to explore the role of ETS1 in mitophagy in BPD and its underlying molecular mechanisms. Using hyperoxia-induced BPD models in cells and mice, we found that ETS1 overexpression simplified alveolar structure, reduced alveolar number, inhibited mitophagy, improved cell viability and mitochondrial damage. Mechanistically, EST1 promoted the transcription of SENP2. After SENP2 removed the SUMO1 modification from FUNDC1, the binding site of HSPA8 was exposed, thereby promoting the degradation of FUNDC1. In BPD mice, ETS1 overexpression alleviated lung injury and inhibited mitophagy, while SENP2 knockdown reversed these effects. In conclusion, ETS1, as a novel transcriptional hub, maintained mitochondrial homeostasis by coordinating the deSUMOylation-coupled FUNDC1 degradation pathway. ETS1 blocked mitochondrial damage-induced mitophagy by targeting the SENP2/HSPA8/FUNDC1 axis, providing a promising strategy for the treatment of BPD.