Ferroportin

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]:

Ferroportin-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]:

See 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

Pathway Diagram

Key molecular relationships involving Ferroportin from the SciDEX knowledge graph:

Pathway Diagram

The following diagram shows the key molecular relationships involving Ferroportin discovered through SciDEX knowledge graph analysis: