Mitochondrial Peptide MOTS-c Protects Lungs from Acute Injury via Ferroptosis Inhibition

Acute lung injury (ALI) is a severe and often life-threatening inflammatory condition characterized by widespread inflammation, impaired gas exchange, and damage to the lung's delicate endothelial barrier. This damage can lead to acute respiratory distress syndrome (ARDS) and has a high mortality rate. While various factors contribute to ALI, the role of specific cell death pathways, such as ferroptosis (a distinct form of programmed cell death characterized by iron-dependent lipid peroxidation), and their interaction with inflammatory receptors like FPR2 (Formyl Peptide Receptor 2), remains complex. This study specifically investigates the involvement of FPR2-mediated ferroptosis in formyl peptide-induced ALI and explores the therapeutic potential of the mitochondria-derived peptide MOTS-c in mitigating endothelial barrier damage.

The study found that MOTS-c significantly attenuated formyl peptide-induced acute lung injury across both in vitro and in vivo models. In the mouse ALI model, MOTS-c treatment at 10 mg/kg resulted in a remarkable 48% reduction in lung edema (wet-to-dry weight ratio) and a 42% decrease in inflammatory cell infiltration into the alveolar spaces compared to untreated ALI controls (p<0.001). Furthermore, MOTS-c effectively suppressed ferroptosis; lipid peroxidation, a key marker of ferroptosis, was reduced by 2.9-fold, while cellular glutathione levels, an antioxidant defense, increased by 3.5-fold in treated lung tissues. > MOTS-c treatment led to a 65% restoration of endothelial barrier integrity in vitro, as measured by transendothelial electrical resistance, and significantly downregulated FPR2 expression by 58% in vivo, demonstrating its direct impact on the injury mechanism. These protective effects were dose-dependent, with the 10 mg/kg dose showing superior efficacy compared to 5 mg/kg in mice, and 100 nM being more effective than 50 nM in cell cultures.