Animal Models of Hereditary Iron Transport Disorders

Andrews, Nancy C.

doi:10.1007/978-1-4615-0593-8_1

Cited by 10 publications

(6 citation statements)

References 87 publications

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“…The Nramp2 mRNA contains IREs and the expression of Nramp2 is regulated post-transcriptionally by the iron level in the body. Defects in Nramp2 (mk mouse and Belgrade rat) lead to the impaired transport of iron and the defective endosomal transport of iron (Andrews 2002;McKie et al 2002). These results indicated that Nramp2 is also involved in the transport of ferrous ion across endosomal membrane into the cytoplasm after the transferrin-iron is released from transferrin in endosomes and reduced by ferrireductase.…”

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 96%

“…In addition, ceruloplasmin, a plasma protein, is required for the export of iron from non-intestinal cells. Ceruloplasmin oxidizes ferrous ion, exported by ferroportin 1, to ferric ion to facilitate the binding of iron to transferrin (Andrews 2002;Lee et al 2002). Humans and mice deficient in ceruloplasmin accumulate iron in several cells including macrophages, neural cells and hepatocytes, indicating that serum ferroxidase activity is essential for the smooth mobilization of iron between macrophages and other tissues.…”

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 99%

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Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

100

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Iron is fastidiously utilized by living cells, since it is an essential element, but is toxic in excess. Cells take up iron via a transferrin-transferrin receptor-dependent endocytotic process. The iron thus taken up is used for essential biological functions including oxygen transport, electron transfer, and DNA synthesis. The intracellular level of iron is tightly controlled, through regulation of the cellular uptake of iron and the sequestering of low molecular labile iron into the storage protein ferritin. The known proteins of iron transport and storage, transferrin, transferrin receptor and ferritin, have been recently linked with a number of newly identified proteins that are responsible for inherited diseases of iron metabolisms and play critical roles in the maintenance of iron homeostasis. These proteins are involved in regulation of intracellular levels of iron, iron transport, and heme transport and the oxygen-dependent regulation of gene expression. On the other hand, most iron is transported into mitochondria and immediately used for the biosynthesis of heme in erythroid cells. The heme biosynthesis in mitochondria is coupled with the supply of iron, and the heme, exported from mitochondria, is utilized as prosthetic groups of hemeproteins. Furthermore, non-erythroid and erythroid cells possess the different regulatory systems for the biosynthesis of heme; iron positively regulates the biosynthesis in erythroid cells while heme negatively regulates it in non-erythroid cells. Because of the toxicity and insolubility of heme, the intracellular level of uncommitted heme is maintained at a low concentration (< 10 -9 M). The influx and efflux of heme also help to prevent cytotoxicity. Finally, heme-binding transcriptional factors such as Bach1 and NPAS2 regulate the transcription of several genes involved in the synthesis and degradation of heme-hemeproteins. The discovery of new molecules related to disorders of iron and heme metabolism is ascribable to a complete mechanistic understanding of the cellular network of iron homeostasis. The network of interactions that link iron and heme metabolisms with functions of cellular regulation involving oxidative stress and inflammations contributes to new insights into clinical aspects of disorders.

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Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 96%

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 99%

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

100

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“…A number of novel genes that play fundamental roles in iron metabolism were identified by mutagenesis screens in zebrafish and mouse [142-144]. The only known vertebrate iron exporter, ferroportin1, was initially discovered through characterizing the zebrafish mutant weissherbst [9].…”

Section: Current Approaches In Identifying Iron Trafficking Regulamentioning

confidence: 99%

Cellular and mitochondrial iron homeostasis in vertebrates

Chen

Paw

2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Iron plays an essential role in cellular metabolism and biological processes. However, due to its intrinsic redox activity, free iron is a potentially toxic molecule in cellular biochemistry. Thus, organisms have developed sophisticated ways to import, sequester, and utilize iron. The transferrin cycle is a well-studied iron uptake pathway that is important for most vertebrate cells. Circulating iron can also be imported into cells by mechanisms that are independent of transferrin. Once imported into erythroid cells, iron is predominantly consumed by the mitochondria for the biosynthesis of heme and iron sulfur clusters. This review focuses on canonical transferrin-mediated and the newly discovered, non-transferrin mediated iron uptake pathways, as well as, mitochondrial iron homeostasis in higher eukaryotes.

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“…In general, insufficiency of porphyrin, iron, or globin impairs hemoglobin production and results in a hypochromic, microcytic anemia. 4,5 Heme, the prosthetic group of hemoglobin, is formed in a series of well-characterized catalytic steps that occur within and outside of mitochondria. The expression of all 8 heme biosynthesis enzymes is up-regulated in terminally differentiating erythroid cells, 6 and erythroid-specific promoters that include GATA1 binding sites are present in most of the heme biosynthetic genes, including 5-aminolevulinic acid synthase 2 (Alas2), which contains several erythroid-specific transcription binding sites, enhancers and DNase hypersensitivity sites in the promoter, and several introns.…”

Section: Introductionmentioning

confidence: 99%

hem6: an ENU-induced recessive hypochromic microcytic anemia mutation in the mouse

Tian

Campagna

Woodward

et al. 2008

Blood

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Mouse models have proven invaluable for understanding erythropoiesis. Here, we describe an autosomal recessive, inherited anemia in the mouse mutant hem6. Hematologic and transplantation analyses reveal a mild, congenital, hypochromic, microcytic anemia intrinsic to the hematopoietic system that is associated with a decreased red blood cell zinc protoporphyrin to heme ratio, indicative of porphyrin insufficiency. Intercross matings show that hem6 can suppress the porphyric phenotype of mice with erythropoietic protoporphyria (EPP). Furthermore, iron uptake studies in hem6 reticulocytes demonstrate defective incorporation of iron into heme that can be partially corrected by the addition of porphyrin precursors. Gene expression and enzymatic assays indicate that erythroid 5-aminolevulinic acid synthase (Alas2) is decreased in hem6 animals, suggesting a mechanism that could account for the anemia. Overall, these data lead to the hypothesis that hem6 encodes a protein that directly or indirectly regulates the expression of Alas2. IntroductionErythroid maturation is a complex process coordinately regulated at multiple levels. 1,2 An array of proteins act in a highly orchestrated manner to control the rapid, global changes in gene expression that occur during erythropoiesis. While the majority of genes are repressed in terminally differentiating erythroid cells, the cellular machinery involved in hemoglobin synthesis is rapidly activated. 3 Coordinated porphyrin biosynthesis, iron acquisition, and globin protein production are required to ensure that these components accumulate in the proper stoichiometry to produce the end product, hemoglobin. In general, insufficiency of porphyrin, iron, or globin impairs hemoglobin production and results in a hypochromic, microcytic anemia. 4,5 Heme, the prosthetic group of hemoglobin, is formed in a series of well-characterized catalytic steps that occur within and outside of mitochondria. The expression of all 8 heme biosynthesis enzymes is up-regulated in terminally differentiating erythroid cells, 6 and erythroid-specific promoters that include GATA1 binding sites are present in most of the heme biosynthetic genes, including 5-aminolevulinic acid synthase 2 (Alas2), which contains several erythroid-specific transcription binding sites, enhancers and DNase hypersensitivity sites in the promoter, and several introns. [5][6][7] Nonetheless, the absence of erythroid-specific promoters in the uroporphyrinogen decarboxylase (Urod) gene and the observation that GATA1 loss-of-function mutations do not reduce the protein levels of porphobilinogen deaminase (Pbgd) suggest that there are other unidentified, perhaps more universal, constituents of the porphyrin biosynthetic enzyme transcriptional regulatory machinery. 8 ALAS2 and ferrochelatase (Fech) are also regulated at the translational level, either directly by intracellular iron or indirectly through iron-sulfur clusters or heme. The 5Ј un-translated region (5ЈUTR) of the Alas2 mRNA contains an iron-responsive element (IRE), and iro...

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Animal Models of Hereditary Iron Transport Disorders

Cited by 10 publications

References 87 publications

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Cellular and mitochondrial iron homeostasis in vertebrates

hem6: an ENU-induced recessive hypochromic microcytic anemia mutation in the mouse

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