Merck
  • Home
  • Search Results
  • Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice.

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

Nature medicine (2016-01-12)
Suzanne M Cloonan, Kimberly Glass, Maria E Laucho-Contreras, Abhiram R Bhashyam, Morgan Cervo, Maria A Pabón, Csaba Konrad, Francesca Polverino, Ilias I Siempos, Elizabeth Perez, Kenji Mizumura, Manik C Ghosh, Harikrishnan Parameswaran, Niamh C Williams, Kristen T Rooney, Zhi-Hua Chen, Monica P Goldklang, Guo-Cheng Yuan, Stephen C Moore, Dawn L Demeo, Tracey A Rouault, Jeanine M D'Armiento, Eric A Schon, Giovanni Manfredi, John Quackenbush, Ashfaq Mahmood, Edwin K Silverman, Caroline A Owen, 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Magna RIP® RNA-Binding Protein Immunoprecipitation Kit, RNA Immunoprecipitation (RIP) Kit containing all necessary reagents to perform 12 individual RNA-binding protein immunoprecipitation (RIP) reactions using protein A/G magnetic beads.
Sigma-Aldrich
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Mitochondria Isolation Kit, sufficient for 10-20 g (animal tissue), sufficient for 50 assays (2 mL), isolation of enriched mitochondrial fraction from animal tissues