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

点击翻译按钮获取中文摘要

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