Effects of mitochondrial biosynthesis regulation through the PGC-1α /ERRα signaling system on the pathogenesis of pulmonary fibrosis

Abstract

Mitochondrial dysfunction has recently been linked to the onset and progression of pulmonary fibrosis. In patients with Idiopathic Pulmonary Fibrosis (IPF), fibroblasts exhibit mitochondrial dysfunction and decreased mitochondrial biogenesis. Estrogen related receptor alpha (ERRα) can upregulate mitochondrial biogenesis by inducing transcriptional regulators for mitochondrial genes. Studies have revealed that ERRα requires the presence of a peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α. The repression of PGC-1α has been demonstrated in the human IPF fibroblasts, leading to decreased mitochondrial biogenesis. However, research on ERR⍺ and PGC-1α/ERR⍺-signaling systems in pulmonary fibrosis has been poorly reported. This study determined whether changes in ERRα affect mitochondrial status and fibroblast to myofibroblast transition (FMT) in vitro. We treated the human fetus lung fibroblast cell line (MRC-5) with TGF-β1 to see the relevance between ERRα and FMT. MRC-5 cells were treated with ERRα inverse agonist (XCT790), and siRNA treatment was performed to determine whether the loss of ERRα results in mitochondrial dysfunction and FMT. To observe the resolution of FMT through enhancing ERRα, human IPF patients’ lung fibroblast cell line (LL97A) were treated with PGC-1α agonists (thyroid hormone, rosiglitazone), and overexpression through pCMV6- ERRα vector were performed. The PGC-1α /ERRα signaling axis and mitochondrial status were decreased in TGF-β1 treated human lung fibroblasts cell lines. The reduction of ERRα have induced FMT and led mitochondrial dysfunction. However, the elevation of ERRα via transfection and drug treatments has reduced FMT and ameliorated mitochondrial dysfunction. Furthermore, anti-fibrotic effects of ERR⍺ was dependent on the coactivator PGC-1α. In this study, we have demonstrated the relevance between the PGC-1α /ERRα signaling system and the pathogenesis of pulmonary fibrosis. FMT was induced by inhibition of ERRα and was enhanced by enhancing ERRα. These findings suggest that the downregulation of ERRα could contribute to pulmonary fibrosis and the resolution of mitochondrial biogenesis through the PGC-1α /ERRα signaling system can ameliorate pulmonary fibrosis through enhancing mitochondrial biogenesis.