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Original article
PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state
  1. Nunzia Caporarello1,
  2. Jeffrey A Meridew1,
  3. Dakota L Jones1,
  4. Qi Tan1,
  5. Andrew J Haak1,
  6. Kyoung M Choi1,
  7. Logan J Manlove2,
  8. Y S Prakash1,2,
  9. Daniel J Tschumperlin1,
  10. Giovanni Ligresti1
  1. 1 Physiology & Biomedical Engineering, Mayo Clinic Minnesota, Rochester, Minnesota, USA
  2. 2 Anesthesiology and Perioperative Medicine, Mayo Clinic Minnesota, Rochester, Minnesota, USA
  1. Correspondence to Dr Giovanni Ligresti, Physiology & Biomedical Engineering, Mayo Clinic Minnesota, Rochester, MN 55905, USA; ligresti{at}bu.edu
  • Present affiliation The present affiliation of Giovanni Ligresti is: Boston University School of Medicine, 72 E. Concord St., E516, MA, 02118, Boston, United States

Abstract

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 PGC1α), 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 PGC1α. In vitro PGC1α 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 PGC1α levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1α expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1α expression fails to recover in aged mice with persistent fibrosis. PGC1α 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 PGC1α in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1α expression and attenuated fibroblast activation. The sustained repression of PGC1α and beneficial effects of its rescue in IPF fibroblasts identifies PGC1α as an important regulator of the fibroblast’s pathological state in IPF.

  • idiopathic pulmonary fibrosis
  • interstitial fibrosis

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Footnotes

  • Contributors NC, DJT and GL designed the study. NC, JAM, DLJ, QT, AJH, LJM and KMC performed experiments. NC, JAM and GL analysed the data. The manuscript was drafted by NC, DJT and GL and revised by NC, YSP, DJT and GL. All authors participated in manuscript preparation and provided final approval of the submitted work.

  • Funding This study was funded by National Heart, Lung, and Blood Institute (HL092961, HL133320, HL142596).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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