Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, The University of Buffalo, Suite 4102, 995 Main St., Buffalo, NY 14203, USA.
Metallomics. 2020 Sep 23;12(9):1323-1334. doi: 10.1039/d0mt00065e.
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.
TBI 或 NTBI。这种通用观点将 TBI 与经典转铁蛋白受体、内体铁摄取以及 NTBI 与由质膜定位的二价金属离子转运体支持的摄取混淆在一起，通常被鉴定为 DMT1。事实上，哺乳动物细胞的铁摄取远比这种有些受限制的观点复杂。这种观点没有考虑到 ZIP8 和 ZIP14 在铁摄取中的重要作用，同时坚持传统的前提，即相对高的内体 [H+] 是从全铁转铁蛋白中释放铁所必需的。铁摄取的经典观点也没有包含这样一个事实，即质膜电子传递 - 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 - 是这一群细胞色素依赖的氧化还原酶的成员，它们将还原当量穿梭穿过质膜。一个不常被人们注意到的事实是，全铁转铁蛋白中铁的还原电位可以被细胞质还原当量 - 还原的吡啶和黄素单核苷酸和二核苷酸以及二氢抗坏血酸 - 接近。这允许在质膜的细胞外表面进行 Fe2+的还原性释放，并随后由中性 pH 转运体 - ZIP 蛋白进行细胞质内转运。这种观点强调的是，有两种 TfR 依赖的摄取途径，一种涉及网格蛋白依赖性、内体小泡运输，另一种不涉及。这就提出了一个问题，即为什么要有两种 Tf，TfR 依赖的铁积累途径。对经典和非经典铁摄取的综述使用脑铁转运作为讨论的切入点，这一焦点鼓励包括铁蛋白作为铁的循环“伴侣”的重要性。
