A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2
A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2
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DOI：
10.1182/bloodadvances.2016003772
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发表时间：
2017-06-01
期刊：
影响因子：
7.5
通讯作者：
Goldfarb, Adam
中科院分区：
文献类型：
--
作者：
Khalil, Shadi;Holy, Maja;Goldfarb, Adam
红系祖细胞是人体内铁的最大消耗者。在这些细胞中，高通量的铁必须到达线粒体基质才能形成足够的血红素来支持血红蛋白化。典型的红系铁运输是通过第一转铁蛋白受体 (TfR1) 介导的二铁转铁蛋白内吞作用进入再循环内体，其中三价铁被释放、还原并通过 DMT1 输出到胞质溶胶。然而，缺乏 TfR1 或 DMT1 的小鼠表现出残留的红细胞生成，这表明铁的利用有其他途径。铁如何从内体转移到线粒体尚不完全清楚，其中涉及胞质伴侣和“亲吻并奔跑”的细胞器间转移。与其旁系同源物 TfR1 相比，TfR2 已在铁感应中发挥作用，但在铁吸收中没有发挥作用。最近，发现骨髓选择性 TfR2 缺陷的小鼠表现出小红细胞增多症，这表明 TfR2 也可能有助于红细胞血红蛋白化。在这项研究中，我们确定了替代运输，其中 TfR2 介导溶酶体转铁蛋白传递。成像研究揭示了红系谱系特异性细胞器排列，由被线粒体巢包围的焦点溶酶体簇组成，这两个细胞器之间有直接接触。红细胞 TfR2 缺乏会导致线粒体形态异常，这表明线粒体维持中依赖 TfR2 的转铁蛋白运输。人类 TFR2 与编码溶酶体铁通道的 MCOLN1 和编码介导细胞器接触的蛋白质的 MFN2 共享谱系和阶段特异性表达模式。功能研究表明，后面这些因子参与线粒体调节和红细胞分化，其中 Mfn2 是线粒体-溶酶体接触所必需的。这些发现确定了红细胞铁运输的新途径，涉及 TfR2 介导的溶酶体递送，随后细胞器间转移至线粒体。
Erythroid progenitors are the largest consumers of iron in the human body. In these cells, a high flux of iron must reach the mitochondrial matrix to form sufficient heme to support hemoglobinization. Canonical erythroid iron trafficking occurs via the first transferrin receptor (TfR1)-mediated endocytosis of diferric-transferrin into recycling endosomes, where ferric iron is released, reduced, and exported to the cytosol via DMT1. However, mice lacking TfR1 or DMT1 demonstrate residual erythropoiesis, suggesting additional pathways for iron use. How iron moves from endosomes to mitochondria is incompletely understood, with both cytosolic chaperoning and " kiss and run" interorganelle transfer implicated. TfR2, in contrast to its paralog TfR1, has established roles in iron sensing, but not iron uptake. Recently, mice with marrow-selective TfR2 deficiency were found to exhibit microcytosis, suggesting TfR2 may also contribute to erythroid hemoglobinization. In this study, we identify alternative trafficking, in which TfR2 mediates lysosomal transferrin delivery. Imaging studies reveal an erythroid lineage-specific organelle arrangement consisting of a focal lysosomal cluster surrounded by a nest of mitochondria, with direct contacts between these 2 organelles. Erythroid TfR2 deficiency yields aberrant mitochondrial morphology, implicating TfR2-dependent transferrin trafficking in mitochondrial maintenance. Human TFR2 shares a lineage-and stage-specific expression pattern with MCOLN1, encoding a lysosomal iron channel, and MFN2, encoding a protein mediating organelle contacts. Functional studies reveal these latter factors to be involved in mitochondrial regulation and erythroid differentiation, with Mfn2 required for mitochondrial-lysosomal contacts. These findings identify a new pathway for erythroid iron trafficking involving TfR2-mediated lysosomal delivery followed by interorganelle transfer to mitochondria.