Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor- beta1 in pulmonary fibrosis

Avignat S. Patel, Jin Woo Song, Sarah G. Chu, Kenji Mizumura, Juan C. Osorio, Ying Shi, Souheil El-Chemaly, Chun Geun Lee, Ivan O. Rosas, Jack A. Elias, Augustine M.K. Choi, Danielle Morse

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Background: Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis. Methods: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. Results: Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/-mice were more susceptible than control mice to bleomycin induced lung fibrosis. Conclusion: TGF- β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.

Original languageEnglish (US)
Article numbere0121246
JournalPLoS ONE
Volume10
Issue number3
DOIs
StatePublished - Mar 18 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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