Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system
Open accessAbstract
Ceruloplasmin (Cp) is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form. A glycosylphosphatidylinositol (GPI)-anchored form of this enzyme is expressed by astrocytes in the mammalian central nervous system, whereas the secreted form is expressed by the liver and found in serum. Lack of this enzyme results in iron accumulation in the brain and neurodegeneration. Herein, we show using astrocytes purified from the central nervous system of Cp-null mice that GPI-Cp is essential for iron efflux and not involved in regulating iron influx. We also show that GPI-Cp colocalizes on the astrocyte cell surface with the divalent metal transporter IREG1 and is physically associated with IREG1. In addition, IREG1 alone is unable to efflux iron from astrocytes in the absence of GPI-Cp or secreted Cp. We also provide evidence that the divalent metal influx transporter DMT1 is expressed by astrocytes and is likely to mediate iron influx into these glial cells. The coordinated actions of GPI-Cp and IREG1 may be required for iron efflux from neural cells, and disruption of this balance could lead to iron accumulation in the central nervous system and neurodegeneration.
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An absence of ceruloplasmin can result in iron accumulation in the brain and neurodegeneration.
“An absence of ceruloplasmin can result in iron accumulation in the brain and neurodegeneration.17”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [17]
The crystal-structure study of apo- or iron-loaded frataxin trimer and 24-subunit homo-oligomer demonstrated architectural similarity between frataxin and ferritin.
“The recent crystal-structure study of apo- or iron-loaded frataxin trimer and 24 subunit homo-oligomer formation demonstrated the architectural similarity between frataxin and ferritin (151).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [151]
The trimer of yeast frataxin binds one atom of iron that constitutes the basic 24-subunit oligomer.
“The trimer of yeast frataxin was shown to bind one atom of iron that constitutes the basic 24-subunit oligomer (151).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [151]
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References 40 · Cited by 377
Research works printed but not linked: 3
- Harris, Z. L., Durley, A. P., Man, T. K., and Gitlin, J. D. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 10812-10817
- Fleming, M. D., Romano, M. A., Su, M. A., Garrick, L. M., Garrick, M. D., and Andrews, N. C. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 1148 -1153
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- Authors
- Jeong, S. Y., & David, S.
- Affiliations
- Montreal General Hospital (CA)
- Corresponding author
- David, Samuel
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-07
- Volume
- 278
- Issue
- 29
- Pages
- 27144-27148
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2060349323
- Cited by
- 377
- References
- 40
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 24 · 2023: 16 · 2022: 12 · 2021: 19 · 2020: 21 · 2019: 16 · 2018: 15 · 2017: 16 · 2016: 7 · 2015: 11 · 2014: 19 · 2013: 17 · 2012: 16
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- ceruloplasmin, glycosylphosphatidylinositol anchoring, iron efflux, astrocytes, DMT1, ferroxidase, iron accumulation, neurodegeneration, central nervous system
- MeSH terms
- Ferroportin, Solute Carrier Family 11, Member 2, Animals, Animals, Newborn, Astrocytes, Base Sequence, Biological Transport, Active, Brain, Ceruloplasmin, DNA, Iron, Nerve Degeneration, Glycosylphosphatidylinositols, Mice, Knockout, Cation Transport Proteins, Iron-Binding Proteins, FMN Reductase, Mice, In Vitro Techniques
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