Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice.
Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice.
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DOI：
10.1038/nm.4021
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发表时间：
2016-02
期刊：
影响因子：
82.9
通讯作者：
Choi AM
中科院分区：
文献类型：
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作者：
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
慢性阻塞性肺疾病（COPD）与吸烟和遗传决定因素均有关。我们先前已确定铁反应元件结合蛋白2（IRP2）是一个重要的COPD易感基因，COPD患者肺部的IRP2蛋白增加。在此我们证明，Irp2缺陷型小鼠可免受香烟烟雾（CS）诱导的实验性COPD的影响。通过整合RIP - Seq、RNA - Seq、基因表达和功能富集聚类分析，我们确定IRP2是肺部线粒体功能的调节因子。IRP2增加了线粒体铁负荷和细胞色素c氧化酶（COX），从而导致线粒体功能障碍以及随后的实验性COPD。线粒体铁负荷较高的弗里德赖希共济失调蛋白（frataxin）缺陷型小鼠在基线状态下气道黏液纤毛清除功能（MCC）受损且肺部炎症更严重，而细胞色素c氧化酶（Sco2）缺陷型小鼠因COX减少而免受CS诱导的肺部炎症和MCC受损。用线粒体铁螯合剂治疗的小鼠或喂食低铁饮食的小鼠可免受CS诱导的COPD。线粒体铁螯合还缓解了已患COPD小鼠的CS对MCC的损害、CS诱导的肺部炎症以及CS相关的肺损伤，这表明线粒体 - 铁轴在COPD中具有关键的功能作用以及潜在的治疗干预价值。
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, with IRP2 protein 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 RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with 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-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.