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Nat. Med., Published online 11 January 2016 | doi:10.1038/nm.4021
Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice
Abstract
Suzanne M Cloonan1,2, Kimberly Glass3.5, Maria E Laucho-Contreras2, Abhiram R Bhashyam2, Morgan Cervo6, Maria A Pabon1, Csaba Konrad7, Francesca Polverino2,8,9, Ilias I Siempos1,10, Elizabeth Perez1, Kenji Mizumura1,2, Manik C Ghosh11, Harikrishnan Parameswaran12, Niamh C Williams1, Kristen T Rooney1, Zhi-Hua Chen2,13, Monica P Goldklang14,15, Guo-Cheng Yuan3,4, Stephen C Moore6, Dawn L Demeo2,5, Tracey A Rouault11, Jeanine M D’Armiento14.16, Eric A Schon17,18, Giovanni Manfredi7, John Quackenbush3.5, Ashfaq Mahmood6, Edwin K Silverman2,5, Caroline A Owen2,8 & Augustine M K Choi1,2
1Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA. 2Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 5Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 6Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA. 8Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA. 9Pulmonary Department, University of Parma, Parma, Italy. 10First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens, Greece. 11Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland, USA. 12Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA. 13Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, China. 14Department of Anesthesiology, Columbia University, New York, New York, USA. 15Department of Medicine, Columbia University, New York, New York, USA. 16Department of Physiology & Cellular Biophysics, Columbia University, New York, New York, USA. 17Department of Neurology, Columbia University Medical Center, New York, New York, USA. 18Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.
Correspondence to : Augustine M K Choi
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.
논문정보
- Research article
- 2016년 01월 (BRIC 등록일 2016-01-20)
- 국외 연구진
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