Non-transferrin-bound iron transporters
Abstract
Most cells in the body acquire iron via receptor-mediated endocytosis of transferrin, the circulating iron transport protein. When cellular iron levels are sufficient, the uptake of transferrin decreases to limit further iron assimilation and prevent excessive iron accumulation. In iron overload conditions, such as hereditary hemochromatosis and thalassemia major, unregulated iron entry into the plasma overwhelms the carrying capacity of transferrin, resulting in non-transferrin-bound iron (NTBI), a redox-active, potentially toxic form of iron. Plasma NTBI is rapidly cleared from the circulation primarily by the liver and other organs (e.g., pancreas, heart, and pituitary) where it contributes significantly to tissue iron overload and related pathology. While NTBI is usually not detectable in the plasma of healthy individuals, it does appear to be a normal constituent of brain interstitial fluid and therefore likely serves as an important source of iron for most cell types in the CNS. A growing body of literature indicates that NTBI uptake is mediated by non-transferrin-bound iron transporters such as ZIP14, L-type and T-type calcium channels, DMT1, ZIP8, and TRPC6. This review provides an overview of NTBI uptake by various tissues and cells and summarizes the evidence for and against the roles of individual transporters in this process.
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This NTBI uptake causes progressive tissue injury, organ failure, and even premature death in untreated affected patients.
“causing progressive tissue injury, organ failure, and even premature death.”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [62]
In affected patients who are not treated, NTBI is taken up avidly through alternative iron transporters in the liver, pancreas, heart and endocrine glands.
“In affected patients who are not treated, NTBI is taken up avidly through alternative iron transporters [62] in the liver, pancreas, heart and endocrine glands”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [62]
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Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis
Nemeth, E., & Ganz, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126493 · Cited by 540 · see citing works
“In affected patients who are not treated, NTBI is taken up avidly through alternative iron transporters [62] in the liver, pancreas, heart and endocrine glands, causing progressive tissue injury, organ failure, and even premature death.”
Background
- Authors
- Knutson, M. D.
- Affiliations
- University of Florida (US)
- Corresponding author
- Knutson, Mitchell D.
- ORCID
- Knutson, Mitchell D.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 133
- Pages
- 101-111
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2897977647
- Cited by
- 221
- References
- 11
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 34 · 2023: 26 · 2022: 30 · 2021: 42 · 2020: 25 · 2019: 13 · 2018: 2
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK080706)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- non-transferrin-bound iron, iron transporters, iron overload, hereditary hemochromatosis, thalassemia major, transferrin, ZIP14, DMT1, ZIP8, TRPC6, L-type calcium channels, T-type calcium channels, brain interstitial fluid
- MeSH terms
- TRPC6 Cation Channel, Hemochromatosis, Humans, Iron, Liver, Transcription Factors, Transferrin, beta-Thalassemia, Ion Transport, Iron Overload, Calcium Channels, L-Type, Calcium Channels, N-Type, Cation Transport Proteins
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