Cloonan, Suzanne M.Glass, KimberlyLaucho-Contreras, Maria E.Bhashyam, AbhiramCervo, MorganPabón, Maria A.Konrad, CsabaPolverino, FrancescaSiempos, Ilias I.Perez, ElizabethMizumura, KenjiGhosh, Manik C.Parameswaran, HarikrishnanWilliams, Niamh C.Rooney, Kristen T.Chen, Zhi-HuaGoldklang, Monica P.Yuan, Guo-ChengMoore, StephenDemeo, DawnRouault, Tracey A.D’Armiento, Jeanine M.Schon, Eric A.Manfredi, GiovanniQuackenbush, JohnMahmood, AshfaqSilverman, EdwinOwen, CarolineChoi, Augustine M.K.2016-08-092015Cloonan, S. M., K. Glass, M. E. Laucho-Contreras, A. R. Bhashyam, M. Cervo, M. A. Pabón, C. Konrad, et al. 2015. “Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice.” Nature medicine 22 (2): 163-174. doi:10.1038/nm.4021. http://dx.doi.org/10.1038/nm.4021.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:27822380Chronic 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, with IRP2 protein 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 RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with 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-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.en-USCOPDMitochondriaIronIRP2LungJournal Article2016-08-0910.1038/nm.4021