Divalent metal transporter-1 decreases metal-related injury in the lung

2005 ◽  
Vol 289 (3) ◽  
pp. L460-L467 ◽  
Author(s):  
Andrew J. Ghio ◽  
Claude A. Piantadosi ◽  
Xinchao Wang ◽  
Lisa A. Dailey ◽  
Jacqueline D. Stonehuerner ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Metal Transport ◽  
Airway Epithelial Cells ◽  
Divalent Metal ◽  
Primary Role ◽  
Airway Epithelial ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Exposure to airborne particulates makes the detoxification of metals a continuous challenge for the lungs. Based on the fate of iron in airway epithelial cells, we postulated that divalent metal transporter-1 (DMT1) participates in detoxification of metal associated with air pollution particles. Homozygous Belgrade rats, which are functionally deficient in DMT1, exhibited diminished metal transport from the lower respiratory tract and greater lung injury than control littermates when exposed to oil fly ash. Preexposure of normal rats to iron in vivo increased expression of the isoform of DMT1 protein that lacked an iron-response element (−IRE), accelerated metal transport out of the lung, and decreased injury after particle exposure. In contrast, normal rats preexposed to vanadium showed less expression of the −IRE isoform of DMT1, decreased metal transport, and greater pulmonary injury after particle instillation. Respiratory epithelial cells in culture gave similar results. Also, DMT1 mRNA and protein expression for the −IRE isoform increased or decreased in these cells when exposed to iron or vanadium, respectively. These results thus demonstrate for the first time a primary role for DMT1 in lung metal transport and detoxification.

TNF, IFN-γ, and endotoxin increase expression of DMT1 in bronchial epithelial cells

2005 ◽  
Vol 289 (1) ◽  
pp. L24-L33 ◽  
Author(s):  
Xinchao Wang ◽  
Michael D. Garrick ◽  
Funmei Yang ◽  
Lisa A. Dailey ◽  
Claude A. Piantadosi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Proinflammatory Cytokines ◽  
Airway Epithelial Cells ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Tnf Α ◽  
Ifn Γ

Regulation of the metal transport protein divalent metal transporter-1 (DMT1) may contribute to the uptake and detoxification of iron by cells resident in the respiratory tract. Inflammation has been associated with an increased availability of this metal resulting in an oxidative stress. Because proinflammatory cytokines and LPS have been demonstrated to affect an elevated expression of DMT1 in a macrophage cell line, we tested the hypothesis that tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and LPS increase DMT1 expression in airway epithelial cells. We used RT-PCR to detect mRNA for both −IRE DMT1 and +IRE DMT1 in BEAS-2B cells. Treatment with TNF-α, IFN-γ, or LPS increased both forms. Western blot analysis also demonstrated an increase in the expression of both isoforms of DMT1 after these treatments. Twenty-four hours after exposure of an animal model to TNF-α, IFN-γ, or LPS, a significant increase in pulmonary expression of −IRE DMT1 was seen by immunohistochemistry; the level of +IRE DMT1 was too low in the lung to be visualized using this methodology. Finally, iron transport into BEAS-2B cells was increased after inclusion of TNF-α, IFN-γ, or LPS in the media. We conclude that proinflammatory cytokines and LPS increase mRNA and protein expression of DMT1 in airway cells in vitro and in vivo. Furthermore, both −IRE and +IRE isoforms are elevated after exposures. Increased expression of this protein appears to be included in a coordinated response of the cell and tissue where the function might be to diminish availability of metal.

scholarly journals Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1

2010 ◽  
Vol 113 (2) ◽  
pp. 454-464 ◽  
Author(s):  
Jerome A. Roth ◽  
Steven Singleton ◽  
Jian Feng ◽  
Michael Garrick ◽  
Prasad N. Paradkar
Keyword(s):  
Proteasomal Degradation ◽  
Metal Transport ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron

2010 ◽  
Vol 432 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Darius J.R. Lane ◽  
Stephen R. Robinson ◽  
Hania Czerwinska ◽  
Glenda M. Bishop ◽  
Alfons Lawen
Keyword(s):  
Iron Uptake ◽  
Divalent Metal ◽  
Iron Accumulation ◽  
Mammalian Brain ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Uptake Pathway ◽  
Cultured Astrocytes

Astrocytes are central to iron and ascorbate homoeostasis within the brain. Although NTBI (non-transferrin-bound iron) may be a major form of iron imported by astrocytes in vivo, the mechanisms responsible remain unclear. The present study examines NTBI uptake by cultured astrocytes and the involvement of ascorbate and DMT1 (divalent metal transporter 1). We demonstrate that iron accumulation by ascorbate-deficient astrocytes is insensitive to both membrane-impermeant Fe(II) chelators and to the addition of the ferroxidase caeruloplasmin. However, when astrocytes are ascorbate-replete, as occurs in vivo, their rate of iron accumulation is doubled. The acquisition of this additional iron depends on effluxed ascorbate and can be blocked by the DMT1 inhibitor ferristatin/NSC306711. Furthermore, the calcein-accessible component of intracellular labile iron, which appears during iron uptake, appears to consist of only Fe(III) in ascorbate-deficient astrocytes, whereas that of ascorbate-replete astrocytes comprises both valencies. Our data suggest that an Fe(III)-uptake pathway predominates when astrocytes are ascorbate-deficient, but that in ascorbate-replete astrocytes, at least half of the accumulated iron is initially reduced by effluxed ascorbate and then imported by DMT1. These results suggest that ascorbate is intimately involved in iron accumulation by astrocytes, and is thus an important contributor to iron homoeostasis in the mammalian brain.

DMT1 expression is increased in the lungs of hypotransferrinemic mice

2003 ◽  
Vol 284 (6) ◽  
pp. L938-L944 ◽  
Author(s):  
Andrew J. Ghio ◽  
Xinchao Wang ◽  
Robert Silbajoris ◽  
Michael D. Garrick ◽  
Claude A. Piantadosi ◽  
...  
Keyword(s):  
Inductively Coupled Plasma ◽  
Airway Epithelial Cells ◽  
Nonheme Iron ◽  
Potential Candidate ◽  
Airway Epithelial ◽  
Wild Type ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Plasma Emission Spectroscopy

Despite a lack of transferrin, hypotransferrinemic (Hp) mice demonstrate an accumulation of iron in peripheral organs including the lungs. One potential candidate for such transferrin-independent uptake of iron is divalent metal transporter-1 (DMT1), an established iron transporter. We tested the hypothesis that increased concentrations of iron in the lungs of Hp mice are associated with elevations in DMT1 expression. With the use of inductively coupled plasma emission spectroscopy, measurements of nonheme iron confirmed significantly elevated concentrations in the lung tissue of Hp mice relative to the wild-type mice. Western blot analyses for the expression of two isoforms of DMT1 in the Hp mice relative to the wild-type animals demonstrated an elevation for the isoform that lacks an iron-responsive element (IRE) with significant decrements in the expression of +IRE DMT1. With the use of immunohistochemistry, −IRE DMT1 was localized to both airway epithelial cells and alveolar macrophages in wild-type mice. Staining appeared increased in both types of cells in the Hp mice. Elevated concentrations of both tissue nonheme iron and expression of −IRE DMT1 in the Hp mice were associated with increased quantities of −IRE mRNA. There was no difference between wild-type and homozygotic Hp mice in the amount of mRNA for DMT1 +IRE. We conclude that differences between Hp and wild-type mice in nonheme iron concentrations were accompanied by increases in the expression of −IRE DMT1. Increased expression of −IRE DMT1 in the lungs of the Hp mice could be responsible for elevated concentrations of the metal in these tissues.

Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat

2001 ◽  
Vol 66 (6) ◽  
pp. 1198-1207 ◽  
Author(s):  
J.R. Burdo ◽  
S.L. Menzies ◽  
I.A. Simpson ◽  
L.M. Garrick ◽  
M.D. Garrick ◽  
...  
Keyword(s):  
Metal Transport ◽  
Divalent Metal ◽  
Transport Protein ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

scholarly journals Membrane-inserted conformation of transmembrane domain 4 of divalent-metal transporter

2003 ◽  
Vol 372 (3) ◽  
pp. 757-766 ◽  
Author(s):  
Hongyan LI ◽  
Fei LI ◽  
Hongzhe SUN ◽  
Zhong Ming QIAN
Keyword(s):  
Transmembrane Domain ◽  
Ph Value ◽  
Structural Features ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Sds Micelles ◽  
Domain 4

Divalent-metal transporter 1 (DMT1) is involved in the intestinal iron absorption and in iron transport in the transferrin cycle. It transports metal ions at low pH (≈5.5), but not at high pH (7.4), and the transport is a proton-coupled process. Previously it has been shown that transmembrane domain 4 (TM4) is crucial for the function of this protein. Here we provide the first direct experimental evidence for secondary-structural features and membrane insertions of a 24-residue peptide, corresponding to TM4 of DMT1 (DMTI-TM4), in various membrane-mimicking environments by the combined use of CD and NMR spectroscopies. The peptide mainly adopts an α-helical structure in trifluoroethanol, SDS and dodecylphosphocholine micelles, and dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol small unilamellar vesicles. It has been demonstrated from both Hα secondary shifts and nuclear-Overhauser-enhancement (NOE) connectivities that the peptide is well folded into an α-helix from Val8 to Lys23 in SDS micelles at pH 4.0, whereas the N-terminus is highly flexible. The α-helical content estimated from NMR data is in agreement with that extracted from CD simulations. The highest helicity was observed in the anionic phospholipids {1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]}, indicating that electrostatic attraction is important for peptide binding and insertion into the membranes. The secondary-structural transition of the peptide occurred at pH 4.3 in the 2,2,2-trifluoroethanol (TFE) water mixed solvent, whereas at a higher pH value (5.6) in SDS micelles, DMT1-TM4 exhibited a more stable structure in SDS micelles than that in TFE in terms of changing the pH and temperature. PAGE did not show high-molecular-mass aggregates in SDS micelles. The position of the peptide relative to SDS micelles was probed by the effects of 5- and 16-doxylstearic acids on the intensities of the peptide proton resonances. The results showed that the majority of the peptide is inserted into the hydrophobic interior of SDS micelles, whereas the C-terminal residues are surface-exposed. The ability of DMT1-TM4 to assume transmembrane features may be crucial for its biological function in vivo.

scholarly journals Divalent Metal Transporter 1 Knock-Down Modulates IL-1β Mediated Pancreatic Beta-Cell Pro-Apoptotic Signaling Pathways through the Autophagic Machinery

2021 ◽  
Vol 22 (15) ◽  
pp. 8013
Author(s):  
Taewook Kang ◽  
Honggang Huang ◽  
Thomas Mandrup-Poulsen ◽  
Martin R. Larsen
Keyword(s):  
Cell Death ◽  
Divalent Metal ◽  
Β Cells ◽  
Β Cell ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Knock Down ◽  
Metal Transporter ◽  
Cell Functions ◽  
Protective Proteins

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.

Does divalent metal transporter 1 mediate the intestinal absorption of arsenic?

2014 ◽  
Vol 229 ◽  
pp. S88
Author(s):  
Zeliha Kayaalti ◽  
Dilek Kaya Akyuzlu ◽  
Vugar Ali Türksoy ◽  
Esma Soylemez ◽  
Tulin Soylemezoglu
Keyword(s):  
Intestinal Absorption ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter
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