NDUFS1 upregulates ENaCα by NAD+ to promote alveolar fluid clearance in acute lung injury.

Alveolar edema and following respiratory distress results in the aggravation of epithelial damage and the progression of acute lung injury (ALI), however, with unclear molecular mechanism remained to be elucidated. Through proteomic screening and scRNA-seq mining analysis, we detected the decline expression of NDUFS1 in epithelial cells in lungs from paraquat/LPS-induced ALI models. NDUFS1 deficiency in alveolar epithelial cells reduced ENaCα expression, which impaired alveolar fluid clearance (AFC) and led to alveolar edema. Mechanistically, NDUSF1 deficiency in alveolar epithelial cells leads to mitochondrial dysfunction such as reduced complex I activity, impaired NAD+ production and increased ROS, these contributed to the decline of ENaCα. Supplementing NAD+ via Olaparib treatment alleviated the reduction of ENaCα abundance raised by NDUFS1 deficiency, improved AFC, and suppressed the progression of ALI. In summary, our study suggests that NDUFS1 promotes AFC by regulating ENaCα via NAD+ in pulmonary epithelial cells during ALI.