Interaction of Transferrin-Endosomes with Mitochondria is Required for Iron Transport to Ferrochelatase in Erythroid Cells

红细胞中铁转运至铁螯合酶需要转铁蛋白内体与线粒体的相互作用

• 批准号: RGPIN-2018-06315
• 负责人: Ponka, Prem
• 金额: $ 2.4万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684790
• 关键词: Interaction; Transferrin; Endosomes; Mitochondria; Required

Normal hemoglobinization of immature red blood cells requires iron (Fe) delivered by plasma transferrin (Tf), mediated by Tf receptors (TfR). Following the binding of diferric-Tf to its cognate receptor on the cell surface, the Tf-TfR complexes are internalized via endocytosis, and Fe is released from Tf by endosomal acidification and reduction by Steap3. Fe2+ is transported across the endosomal membrane by DMT1. The post-endosomal path of Fe within cells is controversial. The prevailing opinion is that a low molecular weight intermediate chaperones Fe transfer from endosomes to mitochondria. However, we have built a concept that, in hemoglobin-producing cells, there is a direct relaying of Fe from the endosomal machinery to that of the mitochondria; we have provided strong evidence for this “kiss and run” model (1). We propose that erythroid precursors have special adaptations that facilitate the high rate of iron transport from endosomes to mitochondria to meet the exceptionally high demand for heme synthesis.***The ultimate goal of this research project is to enhance our knowledge regarding iron and heme metabolism in erythroid cells. In three Specific Aims, we propose to:******1) Identify of the molecular partners involved in the endosme-mitochondria interaction in developing RBC;***2) Examine whether the cytoplasmic domain of TfR also interact with mitochondria;***3) Indentify the signal(s) that determine the attachment/detachment of Tf-endosome with/from mitochondria.******We will use a series of molecular and biochemical approaches in combination with cutting edge technology to analyze the interaction between endosomes and mitochondria and identify the molecular partners involved in these interactions.******We are confident that our proposal will provide strong support for the “kiss-and-run” hypothesis of the intracellular iron trafficking mechanism whereby Tf-containing endosomes cede their iron atoms directly to mitochondria. This investigation will not only enhance our understanding of this pathway, but will also strengthen our knowledge about intracellular trafficking of organelles that represents a “paradigm shift” in cell biology. Therefore, this study will have a strong impact on the academic research in Canada.******1. Hamdi et al. BBA 1863:2859, 2016

未成熟红细胞的正常血红蛋白化需要由 Tf 受体 (TfR) 介导的血浆转铁蛋白 (Tf) 传递的铁 (Fe)。二铁-Tf 与其细胞表面的同源受体结合后，Tf-TfR 复合物通过胞吞作用内化，并且通过内体酸化和 Steap3 还原，从 Tf 中释放 Fe。 Fe2+ 通过 DMT1 跨内体膜转运。 Fe 在细胞内的内体后路径是有争议的。普遍的观点是低分子量中间伴侣 Fe 从内体转移到线粒体。然而，我们建立了一个概念，即在血红蛋白产生细胞中，铁从内体机制直接传递到线粒体机制；我们为这种“接吻就跑”模型提供了强有力的证据 (1)。我们认为红细胞前体具有特殊的适应性，可以促进铁从内体到线粒体的高速率转运，以满足对血红素合成的异常高的需求。***该研究项目的最终目标是增强我们对红细胞中铁和血红素代谢的了解。在三个具体目标中，我们建议：********1) 鉴定参与红细胞发育过程中内质-线粒体相互作用的分子伙伴；***2) 检查 TfR 的胞质结构域是否也与线粒体相互作用；***3) 鉴定决定 Tf-内体与线粒体附着/分离的信号。******我们将使用一系列 分子和生化方法与尖端技术相结合，分析核内体和线粒体之间的相互作用，并确定参与这些相互作用的分子伙伴。******我们相信，我们的建议将为细胞内铁运输机制的“接吻和奔跑”假说提供强有力的支持，即含 Tf 的核内体将其铁原子直接让给线粒体。这项研究不仅将增强我们对这一途径的理解，还将加强我们对代表细胞生物学“范式转变”的细胞内细胞运输的了解。因此，这项研究将对加拿大的学术研究产生重大影响。******1．哈姆迪等人。工商管理学士 1863:2859, 2016