Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

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, with IRP2 protein increased in the lungs of individuals with COPD. Here...

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Hauptverfasser: Cloonan, Suzanne M, Glass, Kimberly, Laucho-Contreras, Maria E, Bhashyam, Abhiram R, Cervo, Morgan, Pabón, Maria A, Konrad, Csaba, Polverino, Francesca, Siempos, Ilias I, Perez, Elizabeth, Mizumura, Kenji, Ghosh, Manik C, Parameswaran, Harikrishnan, Williams, Niamh C, Rooney, Kristen T, Chen, Zhi-Hua, Goldklang, Monica P, Yuan, Guo-Cheng, Moore, Stephen C, Demeo, Dawn L, Rouault, Tracey A, D’Armiento, Jeanine M, Schon, Eric A, Manfredi, Giovanni, Quackenbush, John, Mahmood, Ashfaq, Silverman, Edwin K, Owen, Caroline A, Choi, Augustine M.K
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Sprache:eng
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Zusammenfassung: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, 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.
ISSN:1078-8956
DOI:10.1038/nm.4021