Title: Post-translational regulation of PGC-1α modulates fibrotic repair.
Authors: Larson-Casey, Jennifer L; Gu, Linlin; Davis, Dana; Cai, Guo-Qiang; Ding, Qiang; He, Chao; Carter, A Brent
Published In FASEB J, (2021 06)
Abstract: 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-ɣ (PPARɣ) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α 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-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.
PubMed ID: 34038004
MeSH Terms: Adolescent; Adult; Aged; Animals; Apoptosis; Female; Homeostasis; Humans; Macrophages, Alveolar/metabolism; Macrophages, Alveolar/pathology*; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mitochondria/metabolism; Mitochondria/pathology*; Mitochondrial Dynamics*; Oxidative Stress*; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/chemistry; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*; Phosphorylation; Protein Processing, Post-Translational*; Pulmonary Fibrosis/etiology; Pulmonary Fibrosis/metabolism; Pulmonary Fibrosis/pathology*; Reactive Oxygen Species/metabolism; Signal Transduction; Young Adult