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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.

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Figure 1: Irp2 is pathogenic in experimental COPD.
Figure 2: Novel targets of IRP2 in the lung.
Figure 3: Irp2−/− mice resist CS-induced mitochondrial dysfunction.
Figure 4: IRP2-associated mitochondrial-iron loading and CS exposure.
Figure 5: COX is pathogenic in experimental COPD.
Figure 6: Targeting mitochondrial iron in experimental COPD.

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Acknowledgements

The authors thank J.S. Moon, H.C. Lam, K. Taylor and B. Ding for technical assistance. The authors also acknowledge S. Chan (Harvard Medical School) for the cyto-GRX2 and mito-GRX2 plasmids, Y. Hua (Columbia University) for the breeding of the Sco2ki/ki and Sco2ki/ko mice and J. Connelly (ApoPharma Inc.) for providing Ferriprox. The authors also thank R. Rubio for assistance with RNA-seq, Y. Shao for assistance with the microarray study and M. Ericsson for assistance with transmission electron microscopy. The authors also acknowledge discussion and input from S.W. Ryter, C.A. MacRae and P.Y. Sips. This work was supported by US National Institutes of Health (NIH) grants P01-HL114501 (A.M.K.C.), R01-HL055330 (A.M.K.C.), R01-HL079904 (A.M.K.C.), R01-AI111475-01 (C.A.O.), R01-HL86814 (C.A.O.), R21-HL111835 (C.A.O.), HL122513 (H.P.), R01-HL086936 (to J.M.D'A.) and P01-HD080642 (Project 2 to E.A.S.), NIH–National Heart, Lung and Blood Institute grant K99-HL125899 (S.M.C.), American Lung Association Biomedical Research grant RG-348928 (S.M.C.), a Flight Attendants Medical Research Institute (FAMRI) clinical innovator award (A.M.K.C.), clinical innovator FAMRI grant CIA#123046 (C.A.O.), FAMRI Young Clinical Scientist awards YFEL141004 (F.P.) and YFEL103236 (M.P.G.), and US Department of Defense grant W911F-15-1-0169 (E.A.S.). S.M.C., A.M.K.C., J.Q. and E.K.S. were also supported by NIH grant P01-HL105339 (to E.K.S.). K.G. was supported by NIH grant R01-HL111759 (to J.Q., G.C.Y. and E.K.S.). C.A.O. was also supported by NIH grants R21-ES025379-01 (to A. Fedulov), P01-HL105339 (to E.K.S.) and P01-HL114501 (to A.M.K.C.) and by Brigham and Women's Hospital–Lovelace Respiratory Research institute Research Consortium grants. G.M. and C.K. were supported by NIH grant R01-GM088999 (to G.M.). M.C.G. and T.A.R. acknowledge support from the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Additional support was provided by the Muscular Dystrophy Association (E.A.S.) and the J. Willard and Alice S. Marriott Foundation (E.A.S.).

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S.M.C. and A.M.K.C. conceived and designed the study. S.M.C., K.G., M.E.L.-C., M.A.P., I.I.S., E.P., C.K., K.M., Z.-H.C., N.C.W., K.T.R., M.C.G. and A.M. performed experiments. K.G. analyzed RIP-seq, gene expression and human expression data and performed functional clustering analysis. A.R.B. and M.C. reconstructed and analyzed MCC images. S.C.M. provided technical support for the MCC experiments. C.A.O., F.P. and H.P. analyzed morphometric data. M.C.G. and T.A.R. provided the Irp2−/− mice. E.A.S. provided the Sco2ki/ki and Sco2ki/ko mice, and M.P.G. and J.M.D'A. provided technical support. D.L.D. helped with the LGRC human data set. S.M.C., K.G., G.-C.Y., J.Q., E.K.S., G.M., C.A.O. and A.M.K.C. provided critical analysis and discussions. S.M.C. and A.M.K.C. wrote the paper with significant input and contributions from K.G. and C.A.O. All coauthors reviewed and approved the final manuscript.

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Correspondence to Augustine M K Choi.

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In the past three years, E.K.S. received honoraria and consulting fees from Merck and grant support and consulting fees from GlaxoSmithKline.

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Cloonan, S., Glass, K., Laucho-Contreras, M. et al. Mitochondrial iron chelation ameliorates cigarette smoke–induced bronchitis and emphysema in mice. Nat Med 22, 163–174 (2016). https://doi.org/10.1038/nm.4021

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