Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading.

Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death globally, is influenced by both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as a candidate COPD susceptibility gene based on genetic association studies, with IRP2 increased in the lungs of COPD patients. Here we demonstrate that mice deficient in IRP2 are protected from cigarette smoke (CS)-induced COPD. Using RIP-Seq, RNA-Seq, gene expression and pathway analysis, we identify IRP2 as a regulator of mitochondrial function in the lung. We show that an increase in IRP2 results in a cytochrome c oxidase (COX)-dependent alteration in oxidative capacity and mitochondrial-iron dysfunction involving frataxin. We demonstrate that mice with impaired COX or frataxin activity have altered responses to CS and show that overexpressing IRP2 in vivo alters mitochondrial dynamics. These data suggest a critical role of the mitochondria-iron axis in mediating the pathogenesis of COPD.

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Cloonan SM, Glass K, Laucho-Contreras ME, Bhashyam AR, Cervo M, Pabón MA, Konrad C, Polverino F, Siempos II, Perez E, Mizumura K, Ghosh MC, Parameswaran H, Williams NC, Rooney KT, Chen ZH, Goldklang MP, Yuan GC, Moore SC, Demeo DL, Rouault TA, D'Armiento JM, Schon EA, Manfredi G, Quackenbush J, Mahmood A, Silverman EK, Owen CA, Choi AM