Post-translational regulation of PGC-1α modulates fibrotic repair

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma) coactivator (PGC)-1 alpha. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1 alpha activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1 alpha in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1 alpha maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

Automated summary

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease linked to mitochondrial oxidative stress, with increased mitochondrial biogenesis observed in IPF BAL cells. The nuclear expression of PPAR gamma coactivator-1 alpha (PGC-1 alpha) was found to be elevated in IPF, correlating with reduced pulmonary function. Akt1-mediated regulation of PGC-1 alpha plays a critical role in maintaining mitochondrial homeostasis in monocyte-derived macrophages, promoting apoptosis resistance and contributing to the pathogenesis of pulmonary fibrosis.