A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.
A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.
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DOI：
10.1073/pnas.2121400119
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发表时间：
2022-06-28
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
从贫血到神经退行性疾病，铁分布不均是多种疾病的基础，但缺乏解决这一普遍问题的方法。我们最近报道了一种小分子天然产物，扁树醇，能够在各种缺铁转运体的动物模型中恢复血红蛋白。我们现在表明，扁桃木醇能够系统地重新分配铁，从而恢复铁转运蛋白缺乏小鼠和来自铁转运蛋白疾病患者的原代巨噬细胞中的铁稳态。我们还阐明了扁柏醇介导的铁再分配和生理恢复的逐步机制。总之，这些结果为使用分子修复方法更好地理解和可能治疗铁分布不均匀提供了基础支持。跨膜铁转运蛋白铁转运蛋白（FPN1）的缺乏导致铁的错配，这是导致铁转运蛋白疾病、炎症性贫血和其他一些人类疾病和病症的基础。一种小分子天然产物，扁树醇，最近被证明可以作为一种替代的跨膜铁转运蛋白，在缺乏其他铁转运蛋白的斑马鱼中可以恢复血红蛋白化，并可以增加缺乏fpn1的熨熨铁小鼠的肠道铁吸收。然而，杉木醇是否能够恢复fpn1缺乏动物或患者原代细胞的正常铁生理，以及这种靶向活性的机制尚不清楚。在这里，我们发现扁柏醇可以将铁从肝脏重新分配到熨斗小鼠的红细胞中，从而增加血红蛋白和红细胞压积。机制研究证实，桧木醇作为一种替代的跨膜铁转运体释放被捕获在肝巨噬细胞内的铁，桧木醇-铁复合物将铁转移到转铁蛋白上，由此产生的转铁蛋白-铁复合物以转铁蛋白受体依赖的方式驱动红细胞成熟。我们还发现，在来自运铁蛋白疾病患者的fpn1缺陷原代巨噬细胞中，扁木醇将不稳定的铁从细胞内转移到细胞外，并降低细胞内铁蛋白水平。不稳定铁的动员伴随着细胞内铁蛋白的减少，与受调节的铁蛋白蛋白水解的激活一致。这些发现共同为将小分子铁转运蛋白转化为治疗由铁分布不当引起的人类疾病提供了基础支持。
Iron misdistribution underlies various diseases, ranging from anemia to neurodegeneration, but approaches to addressing this general problem are lacking. We recently reported that a small molecule natural product, hinokitiol, is capable of restoring hemoglobinization in various animal models with missing iron transporters. We now show that hinokitiol is capable of redistributing iron systemically, which in turn restores iron homeostasis in ferroportin-deficient mice and in primary macrophages derived from patients with ferroportin disease. We also elucidated the stepwise mechanism of hinokitiol-mediated iron redistribution and physiological restoration. Together, these results provide foundational support for using a molecular prosthetics approach for better understanding and possibly treating iron misdistribution. Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor–dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.
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影响因子：
3.3
作者：
Ganz T;Nemeth E
通讯作者：
Nemeth E
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
4.8
作者：
Abboud, S;Haile, DJ
通讯作者：
Haile, DJ
DOI：
10.1016/s0300-9629(96)00403-3
发表时间：
1997-09-01
影响因子：
2.3
作者：
Kakuta, K;Orino, K;Watanabe, K
通讯作者：
Watanabe, K
铁转运蛋白下调通过调节多发性骨髓瘤中的 Nrf2-miR-17-5p 轴促进细胞增殖
影响因子：
9
作者：
Kong, Yuanyuan;Hu, Liangning;Shi, Jumei
通讯作者：
Shi, Jumei