Journal
NATURE MEDICINE
Volume 22, Issue 2, Pages 163-174Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4021
Keywords
-
Funding
- US National Institutes of Health (NIH) [P01-HL114501, R01-HL055330, R01-HL079904, R01-A1111475-01, R01-HL86814, R21-HL111835, HL122513, R01-HL086936, P01-HD080642]
- NIH-National Heart, Lung and Blood Institute [K99-HL125899]
- American Lung Association Biomedical Research [RG-348928]
- Flight Attendants Medical Research Institute (FAMRI) clinical innovator award
- clinical innovator FAMRI [CIA 123046]
- FAMRI Young Clinical Scientist a [YFEL141004, YFEL103236]
- US Department of Defense [W911F-15-1-0169]
- NIH [P01-HL114501, P01-HL105339, R01-HL111759, R21-ES025379-01, R01-GM088999]
- Brigham and Women's Hospital-Lovelace Respiratory Research institute Research Consortium
- intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
- Muscular Dystrophy Association
- J. Willard and Alice S. Marriott Foundation
Ask authors/readers for more resources
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 mitochondria! 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 mitochondria! 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available