A holistic view of mammalian (vertebrate) cellular iron uptake.
A holistic view of mammalian (vertebrate) cellular iron uptake.
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DOI：
10.1039/d0mt00065e
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发表时间：
2020-09-23
期刊：
影响因子：
--
通讯作者：
Kosman DJ
中科院分区：
文献类型：
--
作者：
Kosman DJ
哺乳动物的细胞铁摄取通常通过铁是否以转铁蛋白结合的形式呈现给细胞来区分：TBI或NTBI。这种通用的观点将TBI与典型的转铁蛋白受体、内体铁摄取、NTBI与由质膜定位的二价金属离子转运体支持的摄取相结合，最常被识别为DMT1。事实上，哺乳动物细胞对铁的吸收远比这一被禁止的观点所暗示的要微妙得多。这种观点未能适应ZIP8和ZIP14在铁摄取中所起的重要作用，同时坚持了传统的假设，即从全铁转铁蛋白释放铁需要相对较高的内体[H+]热力学。铁摄取的经典观点也不包括这样一个事实，即质膜电子传输-PMET-长期以来一直与细胞铁摄取有关。事实上，已知的哺乳动物金属还原酶-Dcytb和Steap蛋白-是这个依赖细胞色素的氧化还原酶群的成员，这些氧化还原酶在质膜上穿梭还原等价物。一个不被普遍认识的事实是，铁在全铁转铁蛋白中的还原潜力可以被细胞质还原等价物-还原的吡啶和黄素单核苷酸和双核苷酸以及二氢抗坏血酸所接近。这使得Fe2+在质膜的细胞外表面被还原释放，随后通过中性pH转运体-ZIP蛋白-进入细胞质。这一观点强调的是，有两条依赖TFR的摄取途径，一条是依赖TFR的，另一条不涉及依赖于笼蛋白的内溶酶体运输。这就提出了一个问题，即拥有两条依赖Tf、TfR的铁积累途径的选择优势。这篇关于典型和非典型铁摄取的综述使用了脑内铁的运输作为讨论的焦点，这一焦点也鼓励将铁蛋白作为铁铁的循环“伴侣”的重要性包括在内。
Cell iron uptake in mammals is commonly distinguished by whether the iron is presented to the cell as transferrin-bound or not: TBI or NTBI. This generic perspective conflates TBI with canonical transferrin receptor, endosomal iron uptake, and NTBI with uptake supported by a plasma membrane-localized divalent metal ion transporter, most often identified as DMT1. In fact, iron uptake by mammalian cells is far more nuanced than this somewhat proscribed view suggests. This view fails to accommodate the substantial role that ZIP8 and ZIP14 play in iron uptake, while adhering to the traditional premise that a relatively high endosomal [H+] is thermodynamically required for release of iron from holo-Tf. The canonical view of iron uptake also does not encompass the fact that plasma membrane electron transport – PMET – has long been linked to cell iron uptake. In fact, the known mammalian metallo-reductases – Dcytb and the STEAP proteins – are members of this cohort of cytochrome-dependent oxido-reductases that shuttle reducing equivalents across the plasma membrane. A not commonly appreciated fact is the reduction potential of ferric iron in holo-Tf is accessible to cytoplasmic reducing equivalents – reduced pyridine and flavin mono- and di-nucleotides and dihydroascorbic acid. This allows for the reductive release of Fe2+ at the extracellular surface of the PM and subsequent transport into the cytoplasm by a neutral pH transporter – a ZIP protein. What this perspective emphasizes is that there are two TfR-dependent uptake pathways, one which does and one which does not involve clathrin-dependent, endolysosomal trafficking. This raises the question as to the selective advantage of having two Tf, TfR-dependent routes of iron accumulation. This review of canonical and non-canonical iron uptake uses cerebral iron trafficking as a point of discussion, a focus that encourages inclusion also of the importance of ferritin as a circulating ‘chaperone’ of ferric iron.
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