Mitochondria-derived peptide MOTS-c alleviates hyperoxia-induced bronchopulmonary dysplasia in neonatal mice by activating Nrf2 pathway.

Abstract

Oxidative stress play key roles in the pathogenesis of bronchopulmonary dysplasia (BPD). MOTS-c is a mitochondria-derived peptide containing 16 amino acids that is reported to be involved in the treatment of oxidative stress-related diseases. However, whether MOTS-c functions on hyperoxia-induced BPD remains unknown. The purpose of this study was to investigate the potential therapeutic effect and mechanism of MOTS-c on hyperoxia-induced BPD. Here, hyperoxia (70% O) was used to mimic the murine BPD model. We found that MOTS-c content was reduced in hyperoxia-induced BPD mice. Exogenous MOTS-c supplementation alleviated growth retardation, attenuated alveolar simplification, and pulmonary vascular abnormalities in hyperoxia-induced BPD mice. Besides, MOTS-c supplement increased cell viability, inhibited cell death and promoted tube formation in hyperoxia-stimulated HUVECs. Moreover, MOTS-c administration significantly inhibited inflammation and oxidative stress both in vivo and in vitro. In addition, the beneficial effect of MOTS-c was Nrf2 dependent, since the anti-inflammation, anti-oxidative and pro-angiogenic effects of MOTS-c were offset in ML385 (a specific Nrf2 inhibitor) treated HUVECs or in Nrf2 deficiency mice. In conclusion, MOTS-c protects against hyperoxia-induced lung alveolar simplification and abnormal angiogenesis in an Nrf2-dependent manner. MOTS-c emerges as a potential anti-oxidant therapeutic agent to treat hyperoxia-induced BPD.