Just like almost every other disease (except for Mendelian autosomal or recessive disorders), chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. Iron-responsive element–binding protein-2 (IRP2) was previusly identified as an important COPD susceptibility gene. It was shown that IRP2 protein is increased in the lungs of individuals with COPD.
In the present study [below], authors show 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, authors identified IRP2 as a regulator of mitochondrial function in mouse lung. IRP2 increases mitochondrial iron-loading and enhances levels of cytochrome c oxidase (COX), which leads to mitochondrial dysfunction and subsequent experimental COPD.
Frataxin-deficient mice, which have higher mitochondrial iron-loading, show impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice somewhat deficient in synthesis of cytochrome c oxidase, i.e. have lowered COX levels, are 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 also protected from CS-induced COPD. Moreover, mitochondrial iron chelation alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation, and CS-associated lung injury in mice that had established COPD. These exciting findings implicate a critical functional role, and potential therapeutic intervention target, for the mitochondrial-iron axis in COPD.
Nat Med 2o16; 22: 163–174 and editorial in Nature 2o16; 531: 586–587