Regulation of divalent metal transporter 1 (DMT1) non-IRE isoform by the microRNA Let-7d in erythroid cells

Andolfo, Immacolata; Falco, Luigia De; Asci, Roberta; Russo, Roberta; Colucci, Simona; Gorrese, Marisa; Zollo, Massimo; Iolascon, Achille

doi:10.3324/haematol.2009.020685

Cited by 80 publications

(51 citation statements)

References 49 publications

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“…In this work we used K562 erythroleukemia cells for monitoring iron ingress into cytosol and mitochondria and for assessing the effect of cytosolic factors on intracellular iron traffic. We selected these erythroid-myeloid cells because they express an abundant number of functional transferrin receptors and display active iron and heme metabolism (Klausner et al 1983), including inducible hemoglobin synthesis (Andolfo et al 2010). Moreover, these cells have a demonstrable ability to acquire both physiological TfFe (Klausner et al 1983) and non-Tf iron complexes (Lane and Lawen 2008) and can be used for on line monitoring of iron ingress into cytosol and mitochondria by real time fluorescence (Breuer et al 1995;Shvartsman et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Intracellular iron trafficking: role of cytosolic ligands

Shvartsman

Cabantchik

2012

Biometals

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Iron acquired by cells is delivered to mitochondria for metabolic processing via pathways comprising undefined chemical forms. In order to assess cytosolic factors that affect those iron delivery pathways, we relied on microscopy and flow-cytometry for monitoring iron traffic in: (a) K562 erythroleukemia cells labeled with fluorescent metal-sensors targeted to either cytosol or mitochondria and responsive to changes in labile iron and (b) permeabilized cells that retained metabolically active mitochondria accessible to test substrates. Iron supplied to intact cells as transferrin-Fe(III) or Fe(II)-salts evoked concurrent metal ingress to cytosol and mitochondria. With either supplementation modality, iron ingress into cytosol was mostly absorbed by preloaded chelators, but ingress into mitochondria was fully inhibited only by some chelators, indicating different cytosol-to-mitochondria delivery mechanisms. Iron ingress into cytosol or mitochondria were essentially unaffected by depletion of cytosolic iron ligands like glutathione or the hypothesized 2,5 dihydroxybenzoate (2,5-DHBA) siderophore/chaperone. These ligands also failed to affect mitochondrial iron ingress in permeabilized K562 cells suspended in cytosol-simulating medium. In such medium, mitochondrial iron uptake was >6-eightfold higher for Fe(II) versus Fe(III), showed saturable properties and submicromolar K(1/2) corresponding to cytosolic labile iron levels. When measured in iron(II)-containing media, ligands like AMP, ADP or ATP, did not affect mitochondrial iron uptake whereas in iron(III)-containing media ADP and ATP reduced it and AMP stimulated it. Thus, cytosolic iron forms demonstrably contribute to mitochondrial iron delivery, are apparently not associated with DHBA analogs or glutathione but rather with resident components of the cytosolic labile iron pool.

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Section: Introductionmentioning

confidence: 99%

Intracellular iron trafficking: role of cytosolic ligands

Shvartsman

Cabantchik

2012

Biometals

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“…Reticulocytes were isolated from peripheral blood of II.8 patient and healthy controls according to a previously described protocol [25].…”

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confidence: 99%

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

et al. 2012

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Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K 1 ] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval identified-in 20 affected individuals among three multigenerational FP families-two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation did not alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursor cells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase during in vitro erythroid differentiation of CD34 1 erythroid precursors and the erythroleukemia cell lines HEL and K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptide found in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K 1 leak characteristic of this condition. Am. J. Hematol. 88:66-72, 2013. V

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“…Our results show that incubation with a sub-lethal concentration of AbOs reduced the levels of DMT1 (-)IRE mRNA without affecting significantly DMT1 (Andolfo et al 2010). Micro RNAs are short (22 nucleotides) singlestranded RNAs that post-transcriptionally regulate gene expression by binding to imperfect complementary sites within the 3 0 -UTRs of their mRNA targets (Van Wynsberghe et al 2011).…”

Section: Discussionmentioning

confidence: 84%

Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons

et al. 2012

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Two major lesions are pathological hallmarks in Alzheimer's disease (AD): the presence of neurofibrillary tangles formed by intracellular aggregates of the hyperphosphorylated form of the cytoskeletal tau protein, and of senile plaques composed of extracellular aggregates of amyloid beta (Aβ) peptide. Current hypotheses regard soluble amyloid beta oligomers (AβOs) as pathological causative agents in AD. These aggregates cause significant calcium deregulation and mediate neurotoxicity by disrupting synaptic activity. Additionally, the presence of high concentrations of metal ions such as copper, zinc, aluminum and iron in neurofibrillary tangles and senile plaques, plus the fact that they accelerate the rate of formation of Aβ fibrils and AβOs in vitro, suggests that accumulation of these metals in the brain is relevant to AD pathology. A common cellular response to AβOs and transition metals such as copper and iron is the generation of oxidative stress, with the ensuing damage to cellular components. Using hippocampal neurons in primary culture, we report here the effects of treatment with AβOs on the (+)IRE and (-)IRE mRNA levels of the divalent metal transporter DMT1. We found that non-lethal AβOs concentrations decreased DMT1 (-)IRE without affecting DMT1 (+)IRE mRNA levels, and inhibited non-transferrin bound iron uptake. In addition, since both iron and AβOs induce oxidative damage, we studied whether their neurotoxic effects are synergistic. In the range of concentrations and times used in this study, AβOs did not potentiate iron-induced cell death while iron chelation did not decrease AβOs-induced cell death. The lack of synergism between iron and AβOs suggests that these two neurotoxic agents converge in a common target, which initiates signaling processes that promote neurodegeneration.

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Regulation of divalent metal transporter 1 (DMT1) non-IRE isoform by the microRNA Let-7d in erythroid cells

Cited by 80 publications

References 49 publications

Intracellular iron trafficking: role of cytosolic ligands

Intracellular iron trafficking: role of cytosolic ligands

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons

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