The role of endocytic pathways in cellular uptake of plasma non-transferrin iron
Open accessAbstract
BACKGROUND: In transfusional siderosis, the iron binding capacity of plasma transferrin is often surpassed, with concomitant generation of non-transferrin-bound iron. Although implicated in tissue siderosis, non-transferrin-bound iron modes of cell ingress remain undefined, largely because of its variable composition and association with macromolecules. Using fluorescent tracing of labile iron in endosomal vesicles and cytosol, we examined the hypothesis that non-transferrin-bound iron fractions detected in iron overloaded patients enter cells via bulk endocytosis. DESIGN AND METHODS: Fluorescence microscopy and flow cytometry served as analytical tools for tracing non-transferrin-bound iron entry into endosomes with the redox-reactive macromolecular probe Oxyburst-Green and into the cytosol with cell-laden calcein green and calcein blue. Non-transferrin-bound iron-containing media were from sera of polytransfused thalassemia major patients and model iron substances detected in thalassemia major sera; cell models were cultured macrophages, and cardiac myoblasts and myocytes. RESULTS: Exposure of cells to ferric citrate together with albumin, or to non-transferrin-bound iron-containing sera from thalassemia major patients caused an increase in labile iron content of endosomes and cytosol in macrophages and cardiac cells. This increase was more striking in macrophages, but in both cell types was largely reduced by co-exposure to non-transferrin-bound iron-containing media with non-penetrating iron chelators or apo-transferrin, or by treatment with inhibitors of endocytosis. Endosomal iron accumulation traced with calcein-green was proportional to input non-transferrin-bound iron levels (r(2) = 0.61) and also preventable by pre-chelation. CONCLUSIONS: Our studies indicate that macromolecule-associated non-transferrin-bound iron can initially gain access into various cells via endocytic pathways, followed by iron translocation to the cytosol. Endocytic uptake of plasma non-transferrin-bound iron is a possible mechanism that can contribute to iron loading of cell types engaged in bulk/adsorptive endocytosis, highlighting the importance of its prevention by iron chelation.
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Cardiac macrophages may either tailor the delivery of iron to the myocardium or accumulate and detoxify heme which may mainly arise from tissue injury.
“In addition, their roles in the metabolic activity of the adjacent myocardium and in chronic cardiac diseases such as congestive heart failure are increasingly appreciated [199], and macrophages may either tailor the delivery of iron to the myocardium or accumulate and detoxify heme which may mainly arise from tissue injury [161, 214].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [214]
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Self-citation
- Authors
- Sohn, Y.-S., Ghoti, H., Breuer, W., Rachmilewitz, E., Attar, S., Weiss, G., & Cabantchik, Z. I.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Wolfson Medical Center (IL)
- European Hospital (IT)
- Innsbruck Medical University (AT)
- Venue
- Haematologica
- Published
- 2011-12-16
- Volume
- 97
- Issue
- 5
- Pages
- 670-678
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC3342967
- OpenAlex
- W2036415527
- Cited by
- 44
- References
- 37
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 6
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Hebrew University of Jerusalem
- Israel Science Foundation
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- non-transferrin-bound iron, bulk endocytosis, iron overload, thalassemia major, ferric citrate, iron chelation, transferrin, macrophages, cardiomyocytes, iron absorption
- MeSH terms
- Adolescent, Adult, Biological Transport, Cells, Cultured, Cytosol, Endocytosis, Humans, Insulinoma, Iron, Iron Chelating Agents, Macrophages, Microscopy, Fluorescence, Endosomes, Transferrin, Biomarkers, beta-Thalassemia, Myocytes, Cardiac, Young Adult
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