IRP2 in mitochondria required for accumulation of toxic levels of iron in cigarette smokers having COPD

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

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