Lysophosphatidylcholine promotes pulmonary fibrosis following lung injury by facilitating alveolar type 2 cell senescence via Mfsd2a-dependent, Drp1-mediated mitochondrial fission.

Abstract

Idiopathic pulmonary fibrosis (IPF) is widely recognized as a disease originating from alveolar epithelial injury, with senescent alveolar type 2 (AT2) cells playing a key role in the pathogenesis. Previous studies have reported that lysophosphatidylcholine (LPC) levels are abnormally elevated in IPF patients and in mouse models of bleomycin-induced pulmonary fibrosis. However, the role and involved mechanism of LPC in the pathogenesis of pulmonary fibrosis remains unclear. Here, we found that bleomycin-injury increased levels of total LPC, particularly LPC16:0, in both mouse bronchoalveolar lavage fluids (BALF) and AT2 cells during the early stages of the disease. These increased LPC were showed to be closely associated with Mfsd2a upregulation and worsened cellular senescence in AT2 cells. In vitro and in vivo, LPC significantly upregulated expression of Mfsd2a, a known LPC transporter, which enhanced LPC uptake by AT2 cells, leading to intracellular LPC overload. The overloaded LPC enhanced dynamin-related protein 1 (Drp1) phosphorylation at Ser616, inducing excessive mitochondrial fission and mitochondrial ROS (mitoROS) overproduction, which ultimately promoted AT2 cell senescence and pulmonary fibrosis. Importantly, LPC induced mitochondrial fission and cellular senescence in AT2 cells in a Mfsd2a-dependent manner. Furthermore, treatment with Mdivi-1 (an inhibitor of Drp1 phosphorylation) or Mito-TEMPO (a mitochondria-targeted antioxidant) effectively alleviated LPC- or bleomycin-induced AT2 cell senescence. Our results reveal a novel mechanism by which LPC promotes pulmonary fibrosis by facilitating AT2 cell senescence via Mfsd2a-dependent, Drp1-mediated mitochondrial fission. These findings provide new mechanistic insights into lung injury-induced pulmonary fibrosis, suggesting LPC and its regulatory pathways as attractive targets for this disease intervention.