PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha (PPARGC1A, encoding PGC1 alpha), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expression and function of PGC1 alpha. In vitro PGC1 alpha manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation was assessed by quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence and traction force microscopy. Mitochondrial function was assessed by Seahorse analyzer and mitochondria mass and number by flow cytometry, mitochondrial DNA quantification and transmission electron microscopy (TEM). We found that PGC1 alpha levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1 alpha expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1 alpha expression fails to recover in aged mice with persistent fibrosis. PGC1 alpha knockdown alone in normal human lung fibroblasts reduces mitochondrial mass and function while enhancing contractile and matrix synthetic fibroblast activation, senescence-related gene expression and soluble profibrotic and prosenescence signalling. Re-expression of PGC1 alpha in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1 alpha expression and attenuated fibroblast activation. The sustained repression of PGC1 alpha and beneficial effects of its rescue in IPF fibroblasts identifies PGC1 alpha as an important regulator of the fibroblast's pathological state in IPF.