Ferroportin
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ferroportin</th>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">[Hepcidin](/entities/hepcidin)</td>
<td>Binds and induces degradation</td>
</tr>
<tr>
<td class="label">[Ceruloplasmin](/proteins/ceruloplasmin)</td>
<td>Ferroxidase activity</td>
</tr>
<tr>
<td class="label">[Transferrin](/proteins/transferrin-protein)</td>
<td>Iron acceptor</td>
</tr>
<tr>
<td class="label">[DMT1](/proteins/dmt1-protein)</td>
<td>Complementary iron transport</td>
</tr>
<tr>
<td class="label">[Ferritin](/proteins/ferritin-protein)</td>
<td>Storage relationship</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">36 edges</a></td>
</tr>
</table>
Ferroportin is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
...Ferroportin
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ferroportin</th>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">[Hepcidin](/entities/hepcidin)</td>
<td>Binds and induces degradation</td>
</tr>
<tr>
<td class="label">[Ceruloplasmin](/proteins/ceruloplasmin)</td>
<td>Ferroxidase activity</td>
</tr>
<tr>
<td class="label">[Transferrin](/proteins/transferrin-protein)</td>
<td>Iron acceptor</td>
</tr>
<tr>
<td class="label">[DMT1](/proteins/dmt1-protein)</td>
<td>Complementary iron transport</td>
</tr>
<tr>
<td class="label">[Ferritin](/proteins/ferritin-protein)</td>
<td>Storage relationship</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">36 edges</a></td>
</tr>
</table>
Ferroportin is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Ferroportin (also known as SLC40A1, IREG1, or MTP1) is the sole known cellular iron exporter in mammals and plays a central role in systemic iron homeostasis. This transmembrane protein is essential for dietary iron absorption, iron recycling from macrophages, and iron transport across the [blood-brain barrier](/entities/blood-brain-barrier).
Structure and Function
Molecular Architecture
Ferroportin is a 571-amino acid protein with 12 transmembrane domains. The protein forms homodimers and functions as a facilitated transporter, moving ferrous iron (Fe²⁺) across cell membranes in a pH- and temperature-dependent manner[@mckie2000]. Recent cryo-EM structures reveal an inward-open conformation that undergoes conformational changes upon hepcidin binding[@taniguchi2023].
Mechanism of Iron Export
Ferroportin exports Fe²⁺ from cells using a concentration gradient. The export mechanism involves[@ward2012]:
Iron binding: Fe²⁺ binds to the inward-facing conformation
Conformational change: The protein shifts to expose iron to the extracellular space
Iron release: Fe²⁺ is released to extracellular fluid or plasma transferrin
Recycling: The protein returns to inward-facing conformationFerroportin-Hepcidin Axis
Ferroportin is the primary target of [hepcidin](/entities/hepcidin), the master iron-regulatory hormone[@nemeth2004]:
- Hepcidin binds to ferroportin extracellularly
- Triggers ferroportin internalization and lysosomal degradation
- Results in decreased cellular iron export
- This axis is disrupted in neurodegeneration
Role in Neurodegeneration
Blood-Brain Barrier Iron Transport
Ferroportin is expressed on brain endothelial cells and mediates iron efflux from the brain[@rouault2013]. Dysregulation leads to:
- Brain iron accumulation
- Oxidative stress via Fenton chemistry
- Selective vulnerability of iron-rich regions (substantia nigra, basal ganglia)
Ferroptosis and Iron Homeostasis
Ferroportin dysfunction contributes to [ferroptosis](/mechanisms/ferroptosis), an iron-dependent cell death pathway[@stockwell2017]:
- Reduced ferroportin → intracellular iron overload
- Enhanced lipid peroxidation
- Mitochondrial dysfunction
- Cell death characterized by lipid peroxide accumulation
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), ferroportin expression is decreased in dopaminergic [neurons](/entities/neurons)[@ayton2013]:
- Substantia nigra shows iron accumulation
- Ferroportin downregulation worsens iron overload
- Creates feed-forward loop of oxidative damage
- May contribute to selective neuronal vulnerability
Alzheimer's Disease
In [Alzheimer's disease](/diseases/alzheimers-disease), ferroportin dysfunction contributes to pathology[@raha2023]:
- Amyloid plaques contain iron deposits
- Ferroportin expression altered in affected brain regions
- Iron accumulation promotes [Aβ](/proteins/amyloid-beta) aggregation
- [Tau](/proteins/tau) hyperphosphorylation is enhanced by iron
Aceruloplasminemia
[Aceruloplasminemia](/diseases/aceruloplasminemia) demonstrates the critical ferroportin-ceruloplasmin relationship[@miyajima2015]:
- [Ceruloplasmin](/proteins/ceruloplasmin) acts as a ferroportin ferroxidase
- Without ceruloplasmin, iron cannot be oxidized for transferrin binding
- Results in severe brain iron accumulation
- Causes progressive neurodegeneration
Genetic Aspects
SLC40A1 Gene
The SLC40A1 gene encodes ferroportin and is located on chromosome 2q32.2[@pietrangelo2004]. Mutations cause:
- Hereditary hemochromatosis type 4: "Ferroportin disease"
- Loss-of-function mutations cause iron overload
- Some mutations cause hepcidin resistance
Polymorphisms in Neurodegeneration
SLC40A1 polymorphisms have been associated with[@nandar2019]:
- Altered Parkinson's disease risk
- Modified iron accumulation patterns
- Differential response to iron chelation therapy
Therapeutic Implications
Iron Chelation
Ferroportin upregulation is a potential therapeutic strategy[@devos2019]:
- Deferiprone may increase ferroportin expression
- Combination with [deferiprone](/therapeutics/deferiprone-neurodegeneration) therapy
- Enhanced brain iron clearance
Hepcidin Modulation
Targeting the hepcidin-ferroportin axis offers therapeutic potential[@zhou2022]:
- Hepcidin antagonists could increase ferroportin
- Ferroportin stabilizers prevent internalization
- May reduce brain iron in neurodegeneration
Biomarker Potential
Ferroportin levels may serve as a biomarker[@baik2022]:
- CSF ferroportin alterations in disease
- Peripheral ferroportin as indirect marker
- Correlation with brain iron measured by MRI
Interaction with Other Proteins
Research Directions
Current research focuses on[@gao2023]:
Small molecule ferroportin stabilizers
Hepcidin-ferroportin axis modulation
Brain-specific ferroportin targeting
Combination with iron chelation therapy
Ferroportin as a drug delivery targetSee Also
- [ferroptosis](/mechanisms/ferroptosis)
- [Parkinson's disease](/diseases/parkinsons-disease)
- [Alzheimer's disease](/diseases/alzheimers-disease)
- [Aceruloplasminemia](/diseases/aceruloplasminemia)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[McKie AT et al, A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation (2000)](https://pubmed.ncbi.nlm.nih.gov/10748061/)
[Taniguchi R et al, Cryoo-EM structures of human ferroportin in its inward-open and hepcidin-bound states (2023)](https://pubmed.ncbi.nlm.nih.gov/37620897/)
[Ward DM, Kaplan J, Ferroportin-mediated iron transport: expression and regulation (2012)](https://pubmed.ncbi.nlm.nih.gov/22827479/)
[Nemeth E et al, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004)](https://pubmed.ncbi.nlm.nih.gov/14985369/)
[Rouault TA, Iron metabolism in the central nervous system and neurodegenerative disorders (2013)](https://pubmed.ncbi.nlm.nih.gov/23719329/)
[Stockwell BR et al, Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28132922/)
[Ayton S et al, Ferroportin in the substantia nigra in Parkinson's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/24154813/)
[Raha AA et al, The blood-brain barrier in Alzheimer's disease: therapeutic potential of ferroportin (2023)](https://pubmed.ncbi.nlm.nih.gov/37046058/)
[Miyajima H, Aceruloplasminemia (2015)](https://pubmed.ncbi.nlm.nih.gov/25334853/)
[Pietrangelo A, The ferroportin disease (2004)](https://pubmed.ncbi.nlm.nih.gov/15282707/)
[Nandar W, Connor JR, Ferroportin and iron regulation in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30987100/)
[Devos D et al, Targeting brain iron in Parkinson's disease with deferiprone (2019)](https://pubmed.ncbi.nlm.nih.gov/30971061/)
[Zhou Y et al, Hepcidin-ferroportin axis in neurodegenerative disorders (2022)](https://pubmed.ncbi.nlm.nih.gov/35868554/)
[Baik HW et al, Serum ferroportin as a potential biomarker for Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/36410890/)
[Gao G, Li J, Zhang Y, Chang YZ, Cellular iron metabolism and ferroptosis in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/36649190/)Pathway Diagram
Key molecular relationships involving Ferroportin from the SciDEX knowledge graph:
Mermaid diagram (expand to render)
Pathway Diagram
The following diagram shows the key molecular relationships involving Ferroportin discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)