The superoxide-dependent transfer of iron from ferritin to transferrin and lactoferrin.
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ABSTRACT:
SUBMITTER: Monteiro HP
PROVIDER: S-EPMC1135504 | biostudies-other | 1988 Dec
REPOSITORIES: biostudies-other
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Project description:Apo-lactoferrin and apo-transferrin protect against iron-ion-dependent hydroxyl-radical (.OH) generation from H2O2 in the presence of superoxide radicals or ascorbic acid at pH 7.4, whether the necessary iron is added as ionic iron or as ferritin. Iron-loaded transferrin and lactoferrin [2 mol of Fe(III)/mol] show no protective ability, but do not themselves accelerate .OH production unless chelating agents are present in the reaction mixture, especially if the proteins are incorrectly loaded with iron. At acidic pH values, the protective ability of the apoproteins is diminished, and the fully iron-loaded proteins can release some iron in a form able to accelerate .OH generation. The physiological significance of these observations is discussed.
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Project description:Ferritin protein is involved in biological tissues in the storage and management of iron - an essential micro-nutrient in the majority of living systems. While there are extensive studies on iron-loaded ferritin, its functionality in iron delivery is not completely clear. Here, for the first time, differential pulse voltammetry (DPV) has been successfully adapted to address the challenge of resolving a cascade of fast and co-occurring redox steps in enzymatic systems such as ferritin. Using DPV, comparative analysis of ferritins from two evolutionary-distant organisms has allowed us to propose a stepwise resolution for the complex mix of concurrent redox steps that is inherent to ferritins and to fine-tune the structure-function relationship of each redox step. Indeed, the cyclic conversion between Fe3+ and Fe2+ as well as the different oxidative steps of the various ferroxidase centers already known in ferritins were successfully discriminated, bringing new evidence that both the 3-fold and 4-fold channels can be functional in ferritin.
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Project description:Association of a high-serum ferritin with poor outcome showed that iron might play a detrimental role in the brain after intracerebral hemorrhage (ICH). Here, we investigated changes in serum iron, ferritin, transferrin (Tf) and ceruloplasmin (CP) in patients with ICH (n = 100) at day 1 (admission), 3, 7, 14 and 21 and those in control subjects (n = 75). The hematoma and edema volumes were also determined in ICH-patients on admission and at day 3. The Modified Rankin Scale (mRS) of 59 patients was ≥3 (poor outcome) and 41 < 3 (good outcome) at day 90. Serum ferritin was significantly higher and serum iron and Tf markedly lower in patients with poor-outcome than the corresponding values in patients with good-outcome at day 1 to 7 and those in the controls. There was a significant positive correlation between serum ferritin and relative edema volume or ratio at day 1 and 3 and hematoma volume at day 1 (n = 28), and a negative correlation between serum iron or Tf and hematoma volume at day 1 (n = 100). We concluded that not only increased serum ferritin but also reduced serum iron and Tf are associated with outcome as well as hematoma volume.
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Project description:Iron is an essential component of many important proteins and enzymes, including hemoglobin, which is responsible for carrying oxygen to the cells. African Americans (AAs) have a greater prevalence of iron deficiency compared with European Americans. We conducted genome-wide admixture-mapping and association studies for serum iron, serum ferritin, transferrin saturation (SAT) and total iron binding capacity (TIBC) in 2347 AAs participating in the Jackson Heart Study (JHS). Follow-up replication analyses for JHS iron-trait associated SNPs were conducted in 329 AA participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study (HANDLS). Higher estimated proportions of global African ancestry were significantly associated with lower levels of iron (P = 2.4 × 10(-5)), SAT (P = 0.0019) and TIBC (P = 0.042). We observed significant associations (P < 5 × 10(-8)) between serum TIBC levels and two independent SNPs around TF on chromosome 3, the first report of a genome-wide significant second independent signal in this region, and SNPs near two novel genes: HDGFL1 on chromosome 6 and MAF on chromosome 16. We also observed significant associations between ferritin levels and SNPs near GAB3 on chromosome X. We replicated our two independent associations at TF and our association at GAB3 in HANDLS. Our study provides evidence for both shared and unique genetic risk factors that are associated with iron-related measures in AAs. The top two variants in TF explain 11.2% of the total variation in TIBC levels in AAs after accounting for age, gender, body mass index and background ancestry.
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Project description:Iron delivery to the developing brain is essential for energy and metabolic support needed for processes such as myelination and neuronal development. Iron deficiency, especially in the developing brain, can result in a number of long-term neurological deficits that persist into adulthood. There is considerable debate that excess access to iron during development may result in iron overload in the brain and subsequently predispose individuals to age-related neurodegenerative diseases. There is a significant gap in knowledge regarding how the brain acquires iron during development and how biological variables such as development, genetics, and sex impact brain iron status. In this study, we used a mouse model expressing a mutant form of the iron homeostatic regulator protein HFE, (Hfe H63D), the most common gene variant in Caucasians, to determine impact of the mutation on brain iron uptake. Iron uptake was assessed using 59 Fe bound to either transferrin or H-ferritin as the iron carrier proteins. We demonstrate that at postnatal day 22, mutant mice brains take up greater amounts of iron compared with wildtype. Moreover, we introduce H-ferritin as a key protein in brain iron transport during development and identify a sex and genotype effect demonstrating female mutant mice take up more iron by transferrin, whereas male mutant mice take up more iron from H-ferritin at PND22. Furthermore, we begin to elucidate the mechanism for uptake using immunohistochemistry to profile the regional distribution and temporal expression of transferrin receptor and T-cell immunoglobulin and mucin domain 2, the latter is the receptor for H-ferritin. These data demonstrate that sex and genotype have significant effects on iron uptake and that regional receptor expression may play a large role in the uptake patterns during development. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14731.
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Project description:(1) Background: The serum ferritin cut-off to define absolute iron deficiency is not well-established. The aim of the present study was to determine a clinically relevant ferritin threshold by using early serum biomarkers of iron deficiency such as hepcidin and the soluble transferrin receptor; (2) Methods: Two hundred and twenty-eight asymptomatic subjects attending a hospital as outpatients between 1st April 2020 and 27th February 2022 were selected. Iron metabolism parameters as part of the blood analysis were requested by their doctor and included in the study. Then, they were classified into groups according to their ferritin levels and iron-related biomarkers in serum were determined, quantified, and compared between ferritin score groups and anemic subjects. (3) Results: Serum ferritin levels below 50 ng/mL establish the point from which the serum biomarker, the soluble transferrin receptor to hepcidin ratio (sTfR/Hep ratio), begins to correlate significantly with ferritin levels. (4) Conclusion: Ferritin levels ≤ 50 ng/mL are indicative of early iron deficiency; hence, this should be considered as a clinically relevant cut-off for iron deficiency.
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