Enhanced mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness [AT2s RNA-Seq]

Alveolar Type II cells (AT2s) are the stem cells in the alveoli, responsible for both alveolar homeostasis and regeneration. Mitochondrial dysfunction has been reported in the AT2 cells from both chronic and acute injury induced alveolar diseases, including idiopathic pulmonary fibrosis (IPF) and viral pneumonia. Here, we demonstrate that genetic depletion of Ubiquitin Specific Peptidase 30 (USP30), a negative regulator of mitophagy, boosts mitophagy and restores mitochondrial function, leading to protection from injury induced AT2 apoptosis and increased AT2 stem cell activity. Both global Usp30 knockout (KO) and AT2-specific Usp30 KO protects the mice from bleomycin induced lung fibrosis and influenza puneumonia. Moreover, pharmaceutical inhibition of USP30 using a small molecule inhibitor effectively alleviates lung fibrosis and influenza pneumonia. Our study underscores a therapeutic potiential of USP30 inhibition for the treatment of injury induced alveolar diseases, offering a promising strategy for treating injury induced diseases Overall design: RFP+ AT2 cells were flow-sorted from tamoxifen-treated WT-sftpc-creert2 and Usp30-Sftpc-creert2 mice at day 14 after influenza infection