Mitochondrial Pyruvate Metabolism Controls Alveolar Stem Cell Fate and Inflammatory Balance

Alveolar epithelial injury serves as a primary driver of idiopathic pulmonary fibrosis (IPF), where the functional integrity of alveolar type 2 (AT2) cells is essential for lung repair. Mitochondrial pyruvate carrier 2 (Mpc2) is a key component of the pyruvate transport system that sustains mitochondrial oxidative phosphorylation and energy metabolism in AT2 cells. However, the specific role of Mpc2 in AT2 cell function and lung injury remains unclear. Mpc2 expression in AT2 cells was examined in lung tissues from patients with IPF and in mice subjected to bleomycin-induced lung injury. AT2 cell–specific conditional knockout (CKO) mouse models, single-cell transcriptomic analyses, and AT2 organoid cultures were employed to investigate the functional consequences of Mpc2 deficiency during lung injury. Mpc2 expression in AT2 cells was significantly reduced in patients with IPF and in mice following bleomycin-induced lung injury. Conditional deletion of Mpc2 in AT2 cells resulted in decreased expression of the Na⁺/K⁺-ATPase α1 subunit (ATP1A1) and surfactant protein C (SPC), impaired AT2 differentiation during lung injury, and a shift in pulmonary inflammatory profiles toward neutrophil predominance. These changes were associated with increased early mortality in male mice after bleomycin challenge. In contrast, female mice with AT2-specific Mpc2 deletion did not exhibit a significant survival disadvantage but developed more severe pulmonary fibrosis and sustained impairment of AT2 cell differentiation at later stages following bleomycin administration. Mpc2 is essential for maintaining AT2 cell function during lung injury and contributes to the regulation of alveolar epithelial differentiation and inflammatory balance. Targeting Mpc2 may offer novel therapeutic opportunities for lung injury-related diseases.