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Tracey Rouault's Section on Human Iron Metabolism studies mammalian iron metabolism by using mouse models and tissue culture. Rouault previously identified and characterized two major cytosolic iron regulatory proteins (IRPs). Targeted deletion of each IRP in mice revealed that misregulation of iron metabolism due to loss of IRP2 causes functional iron deficiency, erythropoietic protoporphyria, anemia, and neurodegeneration in animals. The Section also focuses on mammalian iron-sulfur cluster assembly, and its researchers have characterized numerous mammalian genes involved in iron-sulfur cluster synthesis, developing in vitro and in vivo methods to assess cluster biogenesis. Their discoveries may promote understanding and treatment of neurodegenerative diseases, especially Parkinson's disease and Friedreich ataxia, and hematologic disorders such as refractory anemias, rare myopathies and erythropoietic protoporphyria.
Regulation of Intracellular Iron Metabolism
Our overall goal is to understand how iron metabolism is regulated in mammals. In cells, iron regulatory proteins 1 and 2 (IRP1 and IRP2) regulate expression of numerous proteins of iron metabolism. In cells that are iron-depleted, these proteins bind to RNA stem-loops in transcripts known as iron-responsive elements (IREs). IRP binding stabilizes the mRNA that encodes transferrin receptor, and represses translation of transcripts that contain IREs near the 5' end such as ferritin H and L chains. IRP1 is an iron-sulfur protein that functions as an aconitase in iron-replete cells. IRP2 is homologous to IRP1, but it undergoes iron-dependent degradation in iron-replete cells. In mouse models, loss of IRP2 results in mild anemia, erythropoietic protoporphyria, and adult-onset neurodegeneration. These phenotypes are likely the result of functional iron deficiency within neurons and red cell precursors. We are studying the mechanisms that lead to anemia and neurodegeneration in IRP2-/- mice using a variety of biochemical assays and expression arrays. In addition, we are using our mouse model of neurodegeneration to identify compounds that can prevent neurodegeneration, and we have found one compound that appears to work. We are evaluating the possibility that loss of IRP2 may cause erythropoietic protoporphyria, adult-onset neurodegeneration and some mild anemias in humans.
Mammalian iron-sulfur cluster biogenesis
The goals of studying mammalian iron-sulfur biogenesis are to understand how iron-sulfur prosthetic groups are assembled and delivered to target proteins in the various compartments of mammalian cells, including mitochondria, cytosol, and nucleus. In addition, we seek to understand the role of iron-sulfur cluster assembly in regulation of mitochondrial iron homeostasis, and to understand the pathogenesis of diseases such as Friedreich ataxia and sideroblastic anemia, in which mitochondrial iron homeostasis is not correctly regulated.
We have identified mammalian homologues of over twenty proteins involved in bacterial and yeast iron-sulfur cluster biogenesis. Three of these genes, including ISCU, frataxin, and glutaredoxin 5 are human disease genes, and a key feature of each disease is mitochondrial iron overload. Using cell lines and tissue from patients, we are working to understand how mitochondrial iron homeostasis is regulated.