Two to Tango: Regulation of Mammalian Iron Metabolism

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Cell (Impact Factor: 32.24). 07/2010; 142(1):24-38. DOI: 10.1016/j.cell.2010.06.028
Source: PubMed

ABSTRACT Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. Iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the iron exporter ferroportin, and another that predominantly controls cellular iron metabolism through iron-regulatory proteins that bind iron-responsive elements in regulated messenger RNAs. We describe how the two distinct systems function and how they "tango" together in a coordinated manner. We also highlight some of the current questions in mammalian iron metabolism and discuss therapeutic opportunities arising from a better understanding of the underlying biological principles.

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Available from: Clara Camaschella, Aug 25, 2014
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    • "The regulation of iron metabolism may be divided into two levels: systemic (distribution of iron among the various tissues of the body) and intracellular. Iron entering a cell is either used for biosynthetic reactions or the unused iron is stored in the cytoplasm or in the mitochondria in the form of ferritin or mitoferrin, or can leave the cell (Hentze et al., 2010). The iron metabolism of the body is orchestrated by hepcidin, the only known iron regulatory hormone (Park et al., 2001). "
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    ABSTRACT: A number of pathophysiological conditions are related to iron metabolism disturbances. Some of them are well known, others are newly discovered or special. Hepcidin is a newly identified iron metabolism regulating hormone which could be a promising biomarker for many disorders. In this review we provide background information about mammalian iron metabolism, cellular iron trafficking and the regulation of expression of hepcidin. Beside these molecular biological processes we summarize the methods which have been used to determine blood and urine hepcidin levels and present those pathological conditions (cancer, inflammation, neurological disorders) when hepcidin measurement may have clinical relevance. This article is protected by copyright. All rights reserved.
    Cell Biology International 06/2015; DOI:10.1002/cbin.10505 · 1.93 Impact Factor
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    • "Indeed, the redox cycling of ferrous and ferric iron in the physiological presence of H 2 O 2 in the cells results in the formation of reactive oxygen intermediates/free radicals (such as hydroxyl radicals) via the Fenton reaction which in turn can damage lipids, DNA, proteins, and other cellular components. Therefore, regulatory interactions between host iron homeostasis (quantity and subcellular location) and immune function are crucial, since both iron deficiency and iron excess can compromise cellular functions [3]. Access to iron is particularly important in the context of host-pathogen interactions. "
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    ABSTRACT: African trypanosomosis is a chronic debilitating disease affecting the health and economic well-being of developing countries. The immune response during African trypanosome infection consisting of a strong proinflammatory M1-type activation of the myeloid phagocyte system (MYPS) results in iron deprivation for these extracellular parasites. Yet, the persistence of M1-type MYPS activation causes the development of anemia (anemia of chronic disease, ACD) as a most prominent pathological parameter in the mammalian host, due to enhanced erythrophagocytosis and retention of iron within the MYPS thereby depriving iron for erythropoiesis. In this review we give an overview of how parasites acquire iron from the host and how iron modulation of the host MYPS affects trypanosomosis-associated anemia development. Finally, we also discuss different strategies at the level of both the host and the parasite that can/might be used to modulate iron availability during African trypanosome infections.
    06/2015; 2015:1-15. DOI:10.1155/2015/819389
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    • "The DMT1 protein , also known as Nramp2 , SLC11A2 , and DCT1 , conducts iron transport at two distinct compartments of the cell : ( 1 ) It facilitates iron uptake at the apical cell membrane in for instance duodenal enterocytes ( Anderson and Vulpe , 2009 ; Hentze et al . , 2010 ; Rouault , 2013 ) ; and ( 2 ) It transports iron across the endosomal membrane in almost all cell types that take up iron via the transferrin - transferrin receptor 1 pathway , e . g . , erythroid precursors in the bone marrow ( Canonne - Hergaux et al . , 2001 ) , and most cells in peripheral tissue . DMT1 functions optimally at an ac"
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    ABSTRACT: Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e. astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail.
    Frontiers in Molecular Neuroscience 05/2015; 8(19). DOI:10.3389/fnmol.2015.00019 · 4.08 Impact Factor
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