Article

Iron Metabolism: Interactions with Normal and Disordered Erythropoiesis

Department of Medicine and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
Cold Spring Harbor Perspectives in Medicine (Impact Factor: 9.47). 05/2012; 2(5):a011668. DOI: 10.1101/cshperspect.a011668
Source: PubMed

ABSTRACT

Hemoglobinopathies and other disorders of erythroid cells are often associated with abnormal iron homeostasis. We review the molecular physiology of intracellular and systemic iron regulation, and the interactions between erythropoiesis and iron homeostasis. Finally, we discuss iron disorders that affect erythropoiesis as well as erythroid disorders that cause iron dysregulation.

Full-text preview

Available from: ncbi.nlm.nih.gov
  • Source
    • "Iron is essential for oxygen transport, oxidation-reduction reactions , and metabolite synthesis (Andrews and Schmidt, 2007; Ganz and Nemeth, 2012). However, because of its high chemical reactivity and ability to generate reactive hydroxyl radicals through Fenton chemistry, iron concentration must be tightly controlled in tissues, cells, and blood (Papanikolaou and Pantopoulos , 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2–3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239–614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.
    Full-text · Article · Jan 2016 · Cell Reports
  • Source
    • "Iron is an indispensable element for all living organisms. Healthy adults contain 4–5 g of iron, about 65% of which is contained in hemoglobin where it participates in oxygen transport, 30–35% is stored in liver, primarily in the storage protein, ferritin, and 1–2% is found in the form of iron–sulfur clusters or heme in the catalytic centers of numerous essential enzymes and multiprotein complexes such as the mitochondrial respiratory chain complexes, which contain twelve iron–sulfur clusters and seven hemes (Hentze et al., 2004; Darshan et al., 2010; Ganz and Nemeth, 2012b; Rouault, 2013). Due to the essential role of iron in vivo, iron deficiency can retard early development and impair cognitive ability of children, and iron deficiency anemia is a common nutrient deficiency disease worldwide. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Iron regulatory proteins (IRPs) regulate the expression of genes involved in iron metabolism by binding to RNA stem-loop structures known as iron responsive elements (IREs) in target mRNAs. IRP binding inhibits the translation of mRNAs that contain an IRE in the 5'untranslated region of the transcripts, and increases the stability of mRNAs that contain IREs in the 3'untranslated region of transcripts. By these mechanisms, IRPs increase cellular iron absorption and decrease storage and export of iron to maintain an optimal intracellular iron balance. There are two members of the mammalian IRP protein family, IRP1 and IRP2, and they have redundant functions as evidenced by the embryonic lethality of the mice that completely lack IRP expression (Irp1 (-/-)/Irp2(-/-) mice), which contrasts with the fact that Irp1 (-/-) and Irp2 (-/-) mice are viable. In addition, Irp2 (-/-) mice also display neurodegenerative symptoms and microcytic hypochromic anemia, suggesting that IRP2 function predominates in the nervous system and erythropoietic homeostasis. Though the physiological significance of IRP1 had been unclear since Irp1 (-/-) animals were first assessed in the early 1990s, recent studies indicate that IRP1 plays an essential function in orchestrating the balance between erythropoiesis and bodily iron homeostasis. Additionally, Irp1 (-/-) mice develop pulmonary hypertension, and they experience sudden death when maintained on an iron-deficient diet, indicating that IRP1 has a critical role in the pulmonary and cardiovascular systems. This review summarizes recent progress that has been made in understanding the physiological roles of IRP1 and IRP2, and further discusses the implications for clinical research on patients with idiopathic polycythemia, pulmonary hypertension, and neurodegeneration.
    Full-text · Article · Jun 2014 · Frontiers in Pharmacology
  • Source
    • "such as transferrin (Tf) [21], transferrin-receptors (TfRs) [22], and ferroportin-1 (Fpn-1) [23]. Within the cell, iron is mainly stored as ferritin [24]. In humans, ferritin is composed of two subunits: ferritin L and ferritin H. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The current study aimed to investigate radiation-induced regulation of iron proteins including ferritin subunits in rats. Rat livers were selectively irradiated in vivo at 25 Gy. This dose can be used to model radiation effects to the liver without inducing overt radiation-induced liver disease. Sham-irradiated rats served as controls. Isolated hepatocytes were irradiated at 8 Gy. Ferritin light polypeptide (FTL) was detectable in the serum of sham-irradiated rats with an increase after irradiation. Liver irradiation increased hepatic protein expression of both ferritin subunits. A rather early increase (3 h) was observed for hepatic TfR1 and Fpn-1 followed by a decrease at 12 h. The increase in TfR2 persisted over the observed time. Parallel to the elevation of AST levels, a significant increase (24 h) in hepatic iron content was measured. Complete blood count analysis showed a significant decrease in leukocyte number with an early increase in neutrophil granulocytes and a decrease in lymphocytes. In vitro, a significant increase in ferritin subunits at mRNA level was detected after irradiation which was further induced with a combination treatment of irradiation and acute phase cytokine. Irradiation can directly alter the expression of ferritin subunits and this response can be strongly influenced by radiation-induced proinflammatory cytokines. FTL can be used as a serum marker for early phase radiation-induced liver damage.
    Full-text · Dataset · Dec 2013
Show more