title: Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Avignat S
authors.initials: AS
authors.lastname: Patel
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Song
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Chu
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Souheil
authors.initials: S
authors.lastname: El-Chemaly
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Alpert Medical School, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Morse
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D001761:Bleomycin; D011494:Protein Kinases; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D000099202:PTEN-Induced Putative Kinase