Frascati-mediated Iron Metabolism in Erythroblasts

$370,508P01FY2009HLNIH

Boston Children'S Hospital, Boston MA

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Abstract

The objective of this proposal is to identify the interacting protein partners and biochemical pathway of the frascati mitochondrial metal transporter and their role in erythroid development. The biochemistry and proteins involved in mitochondrial iron metabolism of developing erythroblasts are poorly understood. Mutations in the zebrafish frascati gene lead to a profound hypochromic anemia and maturation arrest at the pro-erythroblast stage. Using a positional cloning strategy, we showed that the frascati encodes a novel member of the mitochondrial solute carrier family (SLC25). The frascati gene is highly expressed in fetal and adult hematopoietic tissues of zebrafish and mouse. Erythroblasts generated from frascati-null ES cells exhibit maturation arrest with severely impaired incorporation of 55Fe into heme. Mouse mutants generated by targeted disruption of the frascati locus die of severe anemia, thereby confirming its essential role in mammalian erythroid development. We showed that frascati is the major transporter for delivering iron into the mitochondria for heme and Fe-S cluster biosynthesis in developing erythroid cells. The goal of this proposal is to identify the biochemical pathway and interacting protein partners of the frascati transporter to further our understanding of mitochondrial iron metabolism in developing red cells. The identification of frascati as an essential mitochondrial iron transporter and its interacting proteins will provide powerful genetic tools for exploring human disorders of iron metabolism and erythropoiesis. We propose to achieve these aims by the following two specific aims: Specific Aim 1: Protein interacting partners of the frascati transporter will be identified and characterized. Specific Aim 2: A comparative transcriptome analysis of zebrafish embryos and mouse cells deficient for the frascati transporter will be conducted.

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