UNIPROT:P02794 - FACTA Search

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Query: UNIPROT:P02794 (ferritin)
17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial ferritin is a recently identified protein precursor encoded by an intronless gene. It is specifically taken up by the mitochondria and processed to a mature protein that assembles into functional ferritin shells. The full mature recombinant protein and its S144A mutant were produced to study structural and functional properties. They yielded high quality crystals from Mg(II) solutions which diffracted up to 1.38 Angstrom resolution. The 3D structures of the two proteins resulted very similar to that of human H-ferritin, to which they have high level of sequence identity (approximately 80%). Metal-binding sites were identified in the native crystals and in those soaked in Mn(II) and Zn(II) solutions. The ferroxidase center binds binuclear iron at the sites A and B, and the structures showed that the A site was always fully occupied by Mg(II), Mn(II) or Zn(II), while the occupancy of the B site was variable. In addition, distinct Mg(II) and Zn(II)-binding sites were found in the 3-fold axes to block the hydrophilic channels. Other metal-binding sites, never observed before in H-ferritin, were found on the cavity surface near the ferroxidase center and near the 4-fold axes. Mitochondrial ferritin showed biochemical properties remarkably similar to those of human H-ferritin, except for the difficulty in renaturing to yield ferritin shells and for a reduced ( approximately 41%) rate in ferroxidase activity. This was partially rescued by the substitution of the bulkier Ser144 with Ala, which occurs in H-ferritin. The residue is exposed on a channel that connects the ferroxidase center with the cavity. The finding that the mutation increased both catalytic activity and the occupancy of the B site demonstrated that the channel is functionally important. In conclusion, the present data define the structure of human mitochondrial ferritin and provide new data on the iron pathways within the H-type ferritin shell.
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PMID:Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. 1520 Oct 52

In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper/zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin/iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy- and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper/zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes.
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PMID:The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. 1521 Sep 60

Streptococcus suis (S. suis) is an important pathogen in pigs and has to overcome strict iron limitations in its host environment. Here, we studied iron-restricted growth of a highly virulent S. suis strain in vitro at aerobic and CO2-enriched growth conditions. At both conditions, depleting of iron in the culture medium with nitrilotriacetic acid (NTA) resulted in decreased growth rates and down regulation of several proteins. Sensitivity to NTA was significantly higher at aerobic versus CO2-enriched conditions. Growth could not be restored by addition of host iron sources such as ferritin, hemin, hemoglobin, lactoferrin or transferrin. Accordingly, S. suis was not able to produce detectable amounts of siderophores. On the other hand, growth at iron-restricted conditions was fully restored by addition of Mn2+ (at aerobic and CO2-enriched conditions) or Mg2+ (only at CO2-enriched conditions). In conclusion our results suggest that, unlike many other bacteria, S. suis adapts to iron restricted conditions by a change in its metabolism in order to replace Fe2+ by Mn2+ or Mg2+ rather than by expressing specific iron uptake systems.
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PMID:Response of Streptococcus suis to iron-restricted growth conditions at high and low oxygen availability. 1529 52

This study was performed to determine airborne manganese levels during welding practice and to establish the relationship between long-term, low-level exposure to manganese and altered serum concentrations of manganese, iron, and proteins associated with iron metabolism in career welders. Ninety-seven welders (average age of 36 years) who have engaged in electric arc weld in a vehicle manufacturer were recruited as the exposed group. Welders worked 7-8h per day with employment duration of 1-33 years. Control subjects consisted of 91 employees (average age of 35 years) in the same factory but not in the welding profession. Ambient manganese levels in welders' breathing zone were the highest inside the vehicle (1.5 +/- 0.7 mg/m3), and the lowest in the center of the workshop (0.2 +/- 0.05 mg/m3). Since the filter size was 0.8 microm, it is possible that these values may be likely an underestimation of the true manganese levels. Serum levels of manganese and iron in welders were about three-fold (p < 0.01) and 1.2-fold (p < 0.01), respectively, higher than those of controls. Serum concentrations of ferritin and transferrin were increased among welders, while serum transferrin receptor levels were significantly decreased in comparison to controls. Linear regression analyses revealed a lack of association between serum levels of manganese and iron. However, serum concentrations of iron and ferritin were positively associated with years of welder experience (p < 0.05). Moreover, serum transferrin receptor levels were inversely associated with serum manganese concentrations (p < 0.05). These findings suggest that exposure to welding fume among welders disturbs serum homeostasis of manganese, iron, and the proteins associated with iron metabolism. Serum manganese may serve as a reasonable biomarker for assessment of recent exposure to airborne manganese.
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PMID:Alteration of serum concentrations of manganese, iron, ferritin, and transferrin receptor following exposure to welding fumes among career welders. 1571 46

Horse spleen ferritin (HoSF) containing 800-1500 cobalt or 250-1200 manganese atoms as Co(O)OH and Mn(O)OH mineral cores within the HoSF interior (Co-HoSF and Mn-HoSF) was synthesized, and the chemical reactivity, kinetics of reduction, and the reduction potentials were measured. Microcoulometric and chemical reduction of HoSF containing the M(O)OH mineral core (M = Co or Mn) was rapid and quantitative with a reduction stoichiometry of 1.05 +/- 0.10 e/M forming a stable M(OH)(2) mineral core. At pH 9.0, ascorbic acid (AH(2)), a two-electron reductant, effectively reduced the mineral cores; however, the reaction was incomplete and rapidly reached equilibrium. The addition of excess AH(2) shifted the reaction to completion with a M(3+)/AH(2) stoichiometry of 1.9-2.1, consistent with a single electron per metal atom reduction. The rate of reaction between M(O)OH and excess AH(2) was measured by monitoring the decrease in mineral core absorbance with time. The reaction was first order in each reactant with second-order rate constants of 0.53 and 4.74 M(-1) min(-1), respectively, for Co- and Mn-HoSF at pH 9.0. From the variation of absorbance with increasing AH(2) concentration, equilibrium constants at pH 9.0 of 5.0 +/- 1.9 for Co-HoSF and 2.9 +/- 0.9 for Mn-HoSF were calculated for 2M(O)OH + AH(2) = 2M(OH)(2) + D, where AH(2) and D are ascorbic acid and dehydroascorbic acid, respectively. Consistent with these equilibrium constants, the standard potential for the reduction of Co(III)-HoSF is 42 mV more positive than that of the ascorbic acid reaction, while the standard potential of Mn(III)-HoSF is 27 mV positive relative to AH(2). Fe(2+) in solution with Co- and Mn-HoSF under anaerobic conditions was oxidized to form Fe(O)OH within the HoSF interior, resulting in partial displacement of the Co or Mn by iron.
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PMID:Kinetic and thermodynamic characterization of the cobalt and manganese oxyhydroxide cores formed in horse spleen ferritin. 1587 58

Manganese exposure alters iron homeostasis in blood and cerebrospinal fluid (CSF), possibly by acting on iron transport mechanisms localized at the blood-brain barrier and/or blood-CSF barrier. This study was designed to test the hypothesis that manganese exposure may change the binding affinity of iron regulatory proteins (IRPs) to mRNAs encoding transferrin receptor (TfR), thereby influencing iron transport at the blood-CSF barrier. A primary culture of choroidal epithelial cells was adapted to grow on a permeable membrane sandwiched between two culture chambers to mimic blood-CSF barrier. Trace (59)Fe was used to determine the transepithelial transport of iron. Following manganese treatment (100 microM for 24 h), the initial flux rate constant (K(i)) of iron was increased by 34%, whereas the storage of iron in cells was reduced by 58%, as compared to controls. A gel shift assay demonstrated that manganese exposure increased the binding of IRP1 and IRP2 to the stem loop-containing mRNAs. Consequently, the cellular concentrations of TfR proteins were increased by 84% in comparison to controls. Assays utilizing RT-PCR, quantitative real-time reverse transcriptase-PCR, and nuclear run off techniques showed that manganese treatment did not affect the level of heterogeneous nuclear RNA (hnRNA) encoding TfR, nor did it affect the level of nascent TfR mRNA. However, manganese exposure resulted in a significantly increased level of TfR mRNA and reduced levels of ferritin mRNA. Taken together, these results suggest that manganese exposure increases iron transport at the blood-CSF barrier; the effect is likely due to manganese action on translational events relevant to the production of TfR, but not due to its action on transcriptional, gene expression of TfR. The disrupted protein-TfR mRNA interaction in the choroidal epithelial cells may explain the toxicity of manganese at the blood-CSF barrier.
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PMID:Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood-CSF barrier in vitro. 1589 46

The role of the manganese (Mn) oxidation state on cellular Mn uptake and toxicity is not well understood. Therefore, undifferentiated PC12 cells were exposed to 0-200 microM Mn(II)-chloride or Mn(III)-pyrophosphate for 24 h, after which cellular manganese levels were measured along with measures of cell viability, function, and cytotoxicity (trypan blue exclusion, medium lactate dehydrogenase (LDH), 8-isoprostanes, cellular ATP, dopamine, serotonin, H-ferritin, transferrin receptor (TfR), Mn-superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (CuZnSOD) protein levels). Exposures to Mn(III) >10 microM produced 2- to 5-fold higher cellular manganese levels than equimolar exposures to Mn(II). Cell viability and ATP levels both decreased at the highest Mn(II) and Mn(III) exposures (150-200 microM), while Mn(III) exposures produced increases in LDH activity at lower exposures (> or =50 microM) than did Mn(II) (200 microM only). Mn(II) reduced cellular dopamine levels more than Mn(III), especially at the highest exposures (50% reduced at 200 microM Mn(II)). In contrast, Mn(III) produced a >70% reduction in cellular serotonin at all exposures compared to Mn(II). Different cellular responses to Mn(II) exposures compared to Mn(III) were also observed for H-ferritin, TfR, and MnSOD protein levels. Notably, these differential effects of Mn(II) versus Mn(III) exposures on cellular toxicity could not simply be accounted for by the different cellular levels of manganese. These results suggest that the oxidation state of manganese exposures plays an important role in mediating manganese cytotoxicity.
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PMID:Manganese oxidation state mediates toxicity in PC12 cells. 1592 12

Several metal ions that are carcinogenic affect cellular iron homeostasis by competing with iron transporters or iron-regulated enzymes. Some metal ions can mimic a hypoxia response in cells under normal oxygen tension, and induce expression of HIF-1alpha-regulated genes. This study investigated whether 12 metal ions altered iron homeostasis in human lung carcinoma A549 cells as measured by an activation of IRP-1 and ferritin level. We also studied hypoxia signaling by measuring HIF-1alpha protein levels, hypoxia response element (HRE)-driven luciferase reporter activity, and Cap43 protein level (an HIF-1alpha responsive gene). Our results show the following: (i) Ni(II), Co(II), V(V), Mn(II), and to a lesser extent As(III) and Cu(II) activated the binding of IRP-1 to IRE after 24 h, while the other metal ions had no effect; (ii) 10 of 12 metal ions induced HIF-1alpha protein but to strikingly different degrees. Two of these metal ions, Al(III) and Cd(II), did not induce HIF-1alpha protein; however, as indicated below, only Ni(II), Co (II), and to lesser extent Mn(II) and V(V) activated HIF-1alpha-dependent transcription. The combined effects of both [Ni(II) + As(III)] and [Ni(II) + Cr(VI)] on HIF-1alpha protein were synergistic; (iii) Addition of Fe(II) with Ni(II), Co(II), and Cr(VI) attenuated the induction of HIF-1alpha after 4 h treatment; (iv) Ni(II), Co(II), and Mn(II) significantly decrease ferritin level after 24 h exposure; (v) Ni(II), Co(II), V(V), and Mn(II) activated HRE reporter gene after 20 h treatment; (vi) Ni(II), Co(II), V(V), and Mn(II) increased the HIF-1-dependent Cap43 protein level after 24 h treatment. In conclusion, only Ni (II), Co (II), and to a lesser extent Mn(II) and V(V) significantly stabilized HIF-1alpha protein, activated IRP, decreased the levels of ferritin, induced the transcription of HIF-dependent reporter, and increased the expression of Cap43 protein levels (HIF-dependent gene). The mechanism for the significant stabilization and elevation of HIF-1alpha protein which drives these other parameters was previously shown by us and others to involve a loss of cellular Fe as well as inhibition of HIF-1alpha-dependent prolyl hydroxylases which target the binding of VHL ubiquitin ligase and degrade HIF-1alpha. Even though there were small effects of some of the other metals on IRP and HIF-1alpha, downstream effects of HIF-1alpha activation and therefore robust hypoxia signaling were only observed with Ni(II), Co(II), and to much lesser extents with Mn(II) and V(V) in human A549 lung cells. It is of interest that the metal ions that were most effective in activating hypoxia signaling were the ones that were poor inducers of metallothionein protein and also decreased Ferritin levels, since both of these proteins can bind metal ions and protect the cell against toxicity in human lung cells. It is important to study effects of these metals in human lung cells since this represents a major route of human environmental and occupational exposure to these metal ions.
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PMID:Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes. 1638 71

Previous studies in this laboratory indicated that manganese (Mn) exposure in vitro increases the expression of transferrin receptor (TfR) by enhancing the binding of iron regulatory proteins (IRPs) to iron responsive element-containing RNA. The current study further tested the hypothesis that in vivo exposure to Mn increased TfR expression at both blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB), which contributes to altered iron (Fe) homeostasis in the CSF. Groups of rats (10-11 each) received oral gavages at doses of 5 mg Mn/kg or 15 mg Mn/kg as MnCl(2) once daily for 30 days. Blood, CSF, and choroid plexus were collected and brain capillary fractions were separated from the regional parenchyma. Metal analyses showed that oral Mn exposure decreased concentrations of Fe in serum (-66%) but increased Fe in the CSF (+167%). Gel shift assay showed that Mn caused a dose-dependent increase of binding of IRP1 to iron responsive element-containing RNA in BCB in the choroid plexus (+70%), in regional BBB of capillaries of striatum (+39%), hippocampus (+56%), frontal cortex (+49%), and in brain parenchyma of striatum (+67%), hippocampus (+39%) and cerebellum (+28%). Real-time RT-PCR demonstrated that Mn exposure significantly increased the expression of TfR mRNA in choroid plexus and striatum with concomitant reduction in the expression of ferritin (Ft) mRNA. Collectively, these data indicate that in vivo Mn exposure results in Fe redistribution in body fluids through regulating the expression of TfR and ferritin at BCB and selected regional BBB. The disrupted Fe transport by brain barriers may underlie the distorted Fe homeostasis in the CSF.
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PMID:Molecular mechanism of distorted iron regulation in the blood-CSF barrier and regional blood-brain barrier following in vivo subchronic manganese exposure. 1654 56

Manganese (Mn) is an essential trace element, though at elevated exposures it is also a neurotoxicant. Several mechanisms underlying manganese toxicity have been investigated, although a consistent mechanism(s) of action at low exposures has not been fully elucidated. Here we systematically evaluated the effects of in vitro manganese exposure on intracellular iron (Fe) homeostasis and iron-regulatory protein (IRP) binding activity in undifferentiated PC12 cells over a range of manganese exposure concentrations (1, 10, 50, and 200 microM MnCl(2)) and exposure durations (12, 24, 36, and 48 hr), to test the hypothesis that moderately elevated manganese exposure disrupts cellular iron regulation. Results demonstrate that manganese exposure produces a rapid and sustained dose-dependent dysregulation of cellular iron metabolism, with effects occurring as early as 12 hr exposure and at manganese doses as low as 1 microM. Manganese exposure altered the dynamics of IRP-1 binding and the intracellular abundance of IRP-2, and altered the cellular abundance of transferrin receptor, ferritin, and mitochondrial aconitase protein levels. Cellular levels of labile iron were significantly increased with manganese exposure, although total cellular iron levels were not. The overall pattern of effects shows that manganese produced an inappropriate cellular response akin to iron deficiency, to which the cells were able to mount a compensatory response. Consistent with our previous studies, these data indicate that even low to moderate exposures to Manganese in vitro significantly disrupt cellular iron metabolism, which may be an important contributory mechanism of manganese neurotoxicity.
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PMID:Temporal responses in the disruption of iron regulation by manganese. 1656 77

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