Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States.
Medical Sciences Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States.
Am J Physiol Cell Physiol. 2023 May 1;324(5):C1110-C1118. doi: 10.1152/ajpcell.00063.2023. Epub 2023 Mar 20.
Ferroportin (Fpn)-expressed at the plasma membrane of macrophages, enterocytes, and hepatocytes-mediates the transfer of cellular iron into the blood plasma. Under the control of the iron-regulatory hormone hepcidin, Fpn serves a critical role in systemic iron homeostasis. Although we have previously characterized human Fpn, a great deal of research in iron homeostasis and disorders uses mouse models. By way of example, the flatiron mouse, a model of classical ferroportin disease, bears the mutation H32R in Fpn and is characterized by systemic iron deficiency and macrophage iron retention. The flatiron mouse also appears to exhibit a manganese phenotype, raising the possibility that mouse Fpn serves a role in manganese metabolism. At odds with this observation, we have found that human Fpn does not transport manganese, so we considered the possibility that a species difference could explain this discrepancy. We tested the hypothesis that mouse but not human Fpn can transport manganese and performed a comparative analysis of mouse and human Fpn. We examined the functional properties of human Fpn, mouse Fpn, and mutant mouse Fpn by using radiotracer assays in RNA-injected oocytes. We found that neither mouse nor human Fpn transports manganese. Mouse and human Fpn share identical properties with respect to substrate profile, calcium dependence, optimal pH, and hepcidin sensitivity. We have also demonstrated that Fpn is not an ATPase pump. Our findings validate the use of mouse models of ferroportin function in iron homeostasis and disease.
铁蛋白（Fpn）表达于巨噬细胞、肠上皮细胞和肝细胞的质膜上，介导细胞内铁向血浆中的转移。在铁调节激素hepcidin 的控制下，Fpn 在全身铁稳态中起着关键作用。尽管我们之前已经对人 Fpn 进行了特征描述，但铁稳态和紊乱的大量研究使用了小鼠模型。例如，平铁鼠是经典铁蛋白病的模型，其 Fpn 携带 H32R 突变，表现为全身铁缺乏和巨噬细胞铁蓄积。平铁鼠似乎也表现出锰表型，这增加了小鼠 Fpn 可能在锰代谢中发挥作用的可能性。与这一观察结果不一致的是，我们发现人 Fpn 不能转运锰，因此我们考虑这种差异可能是由于物种差异造成的。我们检验了这样一种假设，即小鼠 Fpn 可以转运锰，但人 Fpn 不能，我们对小鼠和人 Fpn 进行了比较分析。我们通过在 RNA 注射卵母细胞中进行放射性示踪剂测定，研究了人 Fpn、小鼠 Fpn 和突变型小鼠 Fpn 的功能特性。我们发现，无论是小鼠还是人 Fpn 都不能转运锰。小鼠和人 Fpn 在底物谱、钙离子依赖性、最佳 pH 值和 hepcidin 敏感性方面具有相同的特性。我们还证明 Fpn 不是一种 ATP 酶泵。我们的研究结果验证了在铁稳态和疾病中使用小鼠模型研究铁蛋白功能的合理性。
