title: Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice.
abstract: Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cloonan
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Laucho-Contreras
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Abhiram R
authors.initials: AR
authors.lastname: Bhashyam
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Cervo
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pabón
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Konrad
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.|Pulmonary Department, University of Parma, Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Polverino
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.|First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Ilias I
authors.initials: II
authors.lastname: Siempos
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Perez
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland, USA.
authors.forename: Manik C
authors.initials: MC
authors.lastname: Ghosh
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
authors.forename: Harikrishnan
authors.initials: H
authors.lastname: Parameswaran
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Niamh C
authors.initials: NC
authors.lastname: Williams
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Kristen T
authors.initials: KT
authors.lastname: Rooney
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Columbia University, New York, New York, USA.|Department of Medicine, Columbia University, New York, New York, USA.
authors.forename: Monica P
authors.initials: MP
authors.lastname: Goldklang
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Moore
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland, USA.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
authors.affiliation: Department of Anesthesiology, Columbia University, New York, New York, USA.|Department of Medicine, Columbia University, New York, New York, USA.|Department of Physiology &Cellular Biophysics, Columbia University, New York, New York, USA.
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.|Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John
authors.identifier: http://orcid.org/0000-0002-2702-5879
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling; D000818:Animals; D001991:Bronchitis / Q000209:etiology / Q000235:genetics*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism; D019266:Iron, Dietary; D033862:Iron-Binding Proteins / Q000235:genetics*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D055370:Lung Injury / Q000209:etiology / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009079:Mucociliary Clearance / Q000235:genetics; D011014:Pneumonia / Q000209:etiology / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000209:etiology / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D014026:Nicotiana; D000096923:Frataxin
chemical_list: D003576:Electron Transport Complex IV; D007501:Iron; D007502:Iron Chelating Agents; D035942:Iron Regulatory Protein 2; D019266:Iron, Dietary; D033862:Iron-Binding Proteins; D012906:Smoke; D000096923:Frataxin