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Might non-transferrin-bound iron in blood plasma and sera be a non-proteinaceous high-molecular-mass Fe^III aggregate?

ABSTRACT: Blood of HFE(-/-) mice and of humans with hemochromatosis contains toxic non-transferrin-bound iron (NTBI) which accumulates in organs. However, the chemical composition of NTBI is uncertain. To investigate, HFE(-/-) mice were fed iron-deficient diets supplemented with increasing amounts of iron, with the expectation that NTBI levels would increase. Blood plasma was filtered to obtain retentate and flow-through-solution (FTS) fractions. Liquid chromatography detected by inductively coupled plasma mass spectrometry of FTSs exhibited low-molecular-mass iron peaks that did not increase intensity with increasing dietary iron. Retentates yielded peaks due to transferrin and ferritin, but much iron in these samples adsorbed onto the column. Retentates treated with deferoxamine (DFO) chelator yielded a peak that comigrated with the Fe-DFO complex and originated from iron that had adhered to the column. Additionally, plasma from younger and older ⁵⁷Fe-enriched HFE mice were separately pooled and concentrated by ultrafiltration. After removing contributions from contaminating blood and transferrin, Mössbauer spectra were dominated by features due to magnetically-interacting Fe^III aggregates, with greater intensity in the spectrum from the older mice. Similar features were generated by adding ⁵⁷Fe^III to "pseudo plasma". Aggregation was unaffected by albumin or citrate at physiological concentrations, but DFO or high citrate concentrations converted aggregated Fe^III into high-spin Fe^III complexes. Fe^III aggregates were retained by the cutoff membrane and adhered to the LC column, similar to NTBI. A model is proposed in which Fe^II entering blood is oxidized, and if apo-transferrin is unavailable, the resulting Fe^III ions coalesce into Fe^III aggregates, a.k.a. NTBI.

SUBMITTER: Vali SW

PROVIDER: S-EPMC9768373 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Might nontransferrin-bound iron in blood plasma and sera be a nonproteinaceous high-molecular-mass Fe<sup>III</sup> aggregate?

Vali Shaik Waseem SW Lindahl Paul A PA

The Journal of biological chemistry 20221109 12

The HFE (Homeostatic Fe regulator) gene is commonly mutated in hereditary hemochromatosis. Blood of (HFE)(-/-) mice and of humans with hemochromatosis contains toxic nontransferrin-bound iron (NTBI) which accumulates in organs. However, the chemical composition of NTBI is uncertain. To investigate, HFE(-/-) mice were fed iron-deficient diets supplemented with increasing amounts of iron, with the expectation that NTBI levels would increase. Blood plasma was filtered to obtain retentate and flow-t ...[more]

PMID: 36334631

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Project description:The molecular mechanisms of iron trafficking in neurons have not been elucidated. In this study, we characterized the expression and localization of ferrous iron transporters Zip8, Zip14 and divalent metal transporter 1 (DMT1), and ferrireductases Steap2 and stromal cell-derived receptor 2 in primary rat hippocampal neurons. Steap2 and Zip8 partially co-localize, indicating these two proteins may function in Fe(3+) reduction prior to Fe(2+) permeation. Zip8, DMT1, and Steap2 co-localize with the transferrin receptor/transferrin complex, suggesting they may be involved in transferrin receptor/transferrin-mediated iron assimilation. In brain interstitial fluid, transferring-bound iron (TBI) and non-transferrin-bound iron (NTBI) exist as potential iron sources. Primary hippocampal neurons exhibit significant iron uptake from TBI (Transferrin-(59) Fe(3+)) and NTBI, whether presented as (59) Fe(2+) -citrate or (59) Fe(3+) -citrate; reductase-independent (59) Fe(2+) uptake was the most efficient uptake pathway of the three. Kinetic analysis of Zn(2+) inhibition of Fe(2+) uptake indicated that DMT1 plays only a minor role in the uptake of NTBI. In contrast, localization and knockdown data indicate that Zip8 makes a major contribution. Data suggest also that cell accumulation of (59) Fe from TBI relies at least in part on an endocytosis-independent pathway. These data suggest that Zip8 and Steap2 play a major role in iron accumulation from NTBI and TBI by hippocampal neurons. Analysis of the expression and localization of known iron uptake transporters demonstrated that Zip8 makes a major contribution to iron accumulation in primary cultures of rat embryonic hippocampal neurons. These cells exhibit uptake pathways for ferrous and ferric iron (non-transferrin-bound iron, NTBI in figure) and for transferrin-bound iron; the ferrireductases Steap2 and SDR2 support the uptake of ferric iron substrates. Zip8 and Steap2 are strongly expressed in the plasma membrane of both soma and processes, implying a crucial role in iron accumulation from NTBI and transferrin-bound iron (TBI) by hippocampal neurons.

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Might non-transferrin-bound iron in blood plasma and sera be a non-proteinaceous high-molecular-mass Fe^III aggregate?

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Might nontransferrin-bound iron in blood plasma and sera be a nonproteinaceous high-molecular-mass Fe<sup>III</sup> aggregate?

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Might non-transferrin-bound iron in blood plasma and sera be a non-proteinaceous high-molecular-mass FeIII aggregate?

Publications

Might nontransferrin-bound iron in blood plasma and sera be a nonproteinaceous high-molecular-mass Fe<sup>III</sup> aggregate?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Might non-transferrin-bound iron in blood plasma and sera be a non-proteinaceous high-molecular-mass Fe^III aggregate?