Frascati-mediated Iron Metabolism in Erythroblasts

$352,354P01FY2008HLNIH

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

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