FPN1 Gene (Ferroportin)
<div class="infobox">
<table>
<tr><td><strong>Symbol</strong></td><td>FPN1</td></tr>
<tr><td><strong>Full Name</strong></td><td>Ferroportin 1</td></tr>
<tr><td><strong>Protein</strong></td><td>[Ferroportin](/entities/ferroportin-protein)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>2q33.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>55730</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>Q9NP73</td></tr>
<tr><td><strong>Aliases</strong></td><td>SLC40A1, FPN1, MTP1, IREG1, SLC11A3</td></tr>
</table>
</div>
Overview
[FPN1](/entities/fpn1) (Ferroportin) encodes the sole known cellular iron exporter in mammals, playing a critical role in systemic iron homeostasis and brain iron metabolism.[@muckenthaler2008] Ferroportin mediates iron efflux from cells, preventing intracellular iron accumulation that can drive oxidative damage through the Fenton reaction.[@ward2014]
Structure and Expression
The FPN1 gene spans approximately 25 kb on chromosome 2q33.1 and contains 8 exons encoding a 571-amino acid protein with 12 predicted transmembrane domains.[@donovan2005] Ferroportin functions as a homodimer at the plasma membrane and is expressed in:
- Enterocytes: Duodenal iron absorption
- Macrophages: Recycling of iron from senescent erythrocytes
- Hepatocytes: Hepatic iron storage and mobilization
- [Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes): Brain iron homeostasis[@mccarthy2013]
Normal Function
...FPN1 Gene (Ferroportin)
<div class="infobox">
<table>
<tr><td><strong>Symbol</strong></td><td>FPN1</td></tr>
<tr><td><strong>Full Name</strong></td><td>Ferroportin 1</td></tr>
<tr><td><strong>Protein</strong></td><td>[Ferroportin](/entities/ferroportin-protein)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>2q33.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>55730</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>Q9NP73</td></tr>
<tr><td><strong>Aliases</strong></td><td>SLC40A1, FPN1, MTP1, IREG1, SLC11A3</td></tr>
</table>
</div>
Overview
[FPN1](/entities/fpn1) (Ferroportin) encodes the sole known cellular iron exporter in mammals, playing a critical role in systemic iron homeostasis and brain iron metabolism.[@muckenthaler2008] Ferroportin mediates iron efflux from cells, preventing intracellular iron accumulation that can drive oxidative damage through the Fenton reaction.[@ward2014]
Structure and Expression
The FPN1 gene spans approximately 25 kb on chromosome 2q33.1 and contains 8 exons encoding a 571-amino acid protein with 12 predicted transmembrane domains.[@donovan2005] Ferroportin functions as a homodimer at the plasma membrane and is expressed in:
- Enterocytes: Duodenal iron absorption
- Macrophages: Recycling of iron from senescent erythrocytes
- Hepatocytes: Hepatic iron storage and mobilization
- [Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes): Brain iron homeostasis[@mccarthy2013]
Normal Function
Ferroportin serves as the primary cellular iron exporter with the following functions:
Iron Export: Transports ferrous iron (Fe²⁺) across cell membranes
HEPCIDIN Regulation: Binds hepcidin, which induces internalization and degradation
Iron Homeostasis: Maintains appropriate cellular iron levels
Placental Iron Transfer: Essential for maternal-fetal iron transport[@drakesmith2015]Role in Neurodegeneration
Brain Iron Homeostasis
Ferroportin is essential for maintaining brain iron balance, working in concert with transferrin receptors, DMT1, and ceruloplasmin to regulate iron trafficking across the [blood-brain barrier](/entities/blood-brain-barrier) and between neural cells.[@moos2007] Dysregulation of ferroportin expression or function contributes to pathological iron accumulation observed in neurodegenerative diseases.
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), iron accumulates in the [substantia nigra](/brain-regions/substantia-nigra) where dopaminergic neurons degenerate. Ferroportin expression is reduced in PD brains, contributing to iron retention and oxidative stress.[@ayton2013] Iron promotes [alpha-synuclein](/proteins/alpha-synuclein) aggregation and enhances neurotoxicity through [ferroptosis](/entities/ferroptosis).
Alzheimer's Disease
[Alzheimer's disease](/diseases/alzheimers-disease) is characterized by iron accumulation in amyloid plaques and neurofibrillary tangles. Ferroportin co-localizes with [amyloid-beta](/proteins/amyloid-beta) plaques, and reduced ferroportin activity may exacerbate iron-mediated oxidative damage and [tau](/proteins/tau) pathology.[@smith2010]
NBIA Type 4
Loss-of-function mutations in FPN1 cause Neurodegeneration with Brain Iron Accumulation Type 4 (NBIA4), an autosomal dominant disorder characterized by progressive iron accumulation in the basal ganglia, cerebellum, and cerebral white matter, leading to movement disorders and cognitive decline.[@de2020]
Molecular Mechanisms
HEPCIDIN-Ferroportin Axis
Hepcidin, the systemic iron regulatory hormone, binds ferroportin and induces its internalization and lysosomal degradation, thereby reducing iron export.[@nemeth2004] In neurodegeneration, elevated hepcidin levels (due to inflammation) may suppress ferroportin, promoting neuronal iron accumulation.
Ferroptosis
Ferroportin dysfunction contributes to ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation. Excess intracellular iron catalyzes the generation of [reactive oxygen species](/entities/reactive-oxygen-species), leading to membrane damage and cell death—a process implicated in PD, AD, and ALS.[@stockwell2017]
Therapeutic Implications
Iron Chelation: Deferiprone and deferoxamine reduce brain iron burden
Hepcidin Antagonism: Blocking hepcidin-ferroportin interaction may restore iron export
Ferroptosis Inhibition: Ferrostatin-1 and liproxstatin-1 prevent iron-dependent cell death
Gene Therapy: Restoring ferroportin expression in affected brain regions[@devos2014]Key Interactions
| Protein | Relationship | Function |
|---------|--------------|----------|
| [HEPCIDIN](/entities/hepcidin) | Ligand | Induces ferroportin internalization |
| [Ceruloplasmin](/entities/ceruloplasmin) | Partner | Oxidizes Fe²⁺ to Fe³⁺ for export |
| DMT1 | Opposing | Imports iron into cells |
| [Ferritin](/entities/ferritin) | Storage | Stores excess cellular iron |
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
- [Allen Human Brain Atlas](https://brain-map.org/)
References
[Muckenthaler MU, Galy B, Hentze MW, Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network (2008)](https://doi.org/10.1146/annurev-genom-090711-163821)
[Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L, The role of iron in brain ageing and neurodegenerative disorders (2014)](https://pubmed.ncbi.nlm.nih.gov/24789079/)
[Donovan A, Lima CA, Pinkus JL, et al, The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis (2005)](https://pubmed.ncbi.nlm.nih.gov/15814858/)
[McCarthy RC, Kosman DJ, Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux (2013)](https://pubmed.ncbi.nlm.nih.gov/23291873/)
[Drakesmith H, Nemeth E, Ganz T, Ironing out Ferroportin (2015)](https://doi.org/10.1016/j.ccell.2015.07.006)
[Moos T, Rosengren Nielsen T, Skjørringe T, Morgan EH, Iron trafficking inside the brain (2007)](https://pubmed.ncbi.nlm.nih.gov/17991602/)
[Ayton S, Lei P, Duce JA, et al, Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23954917/)
[Smith MA, Zhu X, Tabaton M, et al, Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment (2010)](https://pubmed.ncbi.nlm.nih.gov/21054330/)
[De Falco L, Silvestri L, Kannengiesser C, et al, Functional and clinical impact of novel ferroportin mutations (2020)](https://pubmed.ncbi.nlm.nih.gov/31342532/)
[Nemeth E, Tuttle MS, Powelson J, et al, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004)](https://doi.org/10.1126/science.1104742)
[Stockwell BR, Friedmann Angeli JP, Bayir H, et al, Ferroptosis: A Regulated Cell Death Nexus Connecting Metabolism, Redox Biology, and Disease (2017)](https://doi.org/10.1016/j.cell.2017.09.021)
[Devos D, Moreau C, Devedjian JC, et al, Targeting chelatable iron as a therapeutic modality in Parkinson's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24864761/)Pathway Diagram
The following diagram shows the key molecular relationships involving FPN1 (Ferroportin) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)