Ferroportin (SLC40A1)

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protein909 wordssynced 2026-04-02

Ferroportin (SLC40A1)

<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>SLC40A1</td></tr>
<tr><td><strong>UniProt</strong></td><td>[Q9NP59](https://www.uniprot.org/uniprot/Q9NP59)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>70 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, Endosomes</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>[6VYH](https://www.rcsb.org/structure/6VYH) (zebrafish)</td></tr>
<tr><td><strong>Aliases</strong></td><td>FPN, IREG1, MTP1, SLC40A1</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>
</div>

Overview

...

Ferroportin (SLC40A1)

Overview

Mermaid diagram (expand to render)

Ferroportin (SLC40A1), also known as IREG1 or MTP1, is the sole known mammalian iron exporter responsible for transporting ferrous iron (Fe2+) out of cells. Working in concert with its regulatory partner hepcidin, ferroportin plays a central role in systemic iron homeostasis and is increasingly implicated in neurodegenerative diseases where iron export dysfunction contributes to pathological iron accumulation.[@mckie2000]

Structure and Domains

Ferroportin is a 571-amino acid multi-pass transmembrane protein:[@dautryvarsat2020]

Structural features:

12-16 transmembrane helices: Exact topology debated; recent cryo-EM structures show 12 TMs
N-terminal cytoplasmic domain: Contains regulatory phosphorylation sites
Hephaestin/ceruloplasmin binding site: Enables Fe²⁺ oxidation upon export
Hepcidin binding site: Extracellular loop between TM5 and TM6

The cryo-EM structure (from zebrafish) reveals:

Central cavity for iron translocation
Two iron binding sites per transporter
Conformational changes upon hepcidin binding

Normal Function

Ferroportin serves as the cellular iron export channel:[@drakesmith2012]

Iron export pathway:

Ferroportin transports Fe²⁺ from intracellular stores to extracellular space
Requires a ferroxidase partner (hephaestin in enterocytes, ceruloplasmin in CNS)
Fe²⁺ is oxidized to Fe³⁺ for binding to transferrin

Hepcidin regulation:

Hepcidin, produced by the liver, binds ferroportin
Triggers ferroportin internalization and degradation
Creates a negative feedback loop for iron homeostasis
Iron loading → hepcidin ↑ → ferroportin ↓ → iron absorption ↓

Cellular distribution:

Enterocytes: DMT1 imports → ferroportin exports dietary iron
Macrophages: Recycle iron from senescent red blood cells
Hepatocytes: Store and release iron
[Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes): Export iron to maintain homeostasis

Transport mechanism:

Fe²⁺ (intracellular) → Fe²⁺ (extracellular)
Coupled with H⁺ movement (antiport)

Role in Neurodegeneration

Neurodegeneration with Brain Iron Accumulation (NBIA)

Ferroportin dysfunction is directly implicated in NBIA disorders:[@levi2021]

Ferroportin Disease (Type 4 Hemochromatosis):

Caused by SLC40A1 mutations (loss-of-function or dominant-negative)
Results in iron accumulation in specific cell types
Some mutations cause neurological symptoms

Aceruloplasminemia:

Ceruloplasmin mutations impair ferroportin function
Iron accumulates in brain (basal ganglia, cerebellum)
Progressive neurodegeneration with dementia and movement disorders
Demonstrates ferroportin-ceruloplasmin coupling is essential in CNS[@miyajima2015]

Parkinson's Disease

Ferroportin's role in PD iron accumulation:[@raha2013]

Ferroportin expression is reduced in substantia nigra dopaminergic neurons
Hepcidin is elevated in PD brain, promoting ferroportin degradation
Iron export capacity is compromised, contributing to iron accumulation
α-Synuclein aggregates may interfere with ferroportin trafficking

Mechanistic model:
Aging/α-Synuclein → Hepcidin ↑ → Ferroportin degradation →
Iron export ↓ → Iron accumulation → Fenton chemistry → Neuron death

Alzheimer's Disease

Ferroportin dysfunction in AD:[@raha2020]

Altered ferroportin expression in AD brain tissue
Amyloid plaques show iron accumulation
Hepcidin levels are altered in AD CSF
Ferroportin-ceruloplasmin axis disruption may contribute to oxidative stress

Multiple Sclerosis

Ferroportin expression is altered in MS lesions
Iron accumulation in activated [microglia](/cell-types/microglia-neuroinflammation)
Hepcidin upregulation may impair iron export from lesion sites

Therapeutic Targeting

Hepcidin Antagonism

Strategies to preserve ferroportin function:[@sun2012]

| Strategy | Mechanism | Status |
|----------|-----------|--------|
| Anti-hepcidin antibodies | Block hepcidin-ferroportin binding | Clinical trials (anemia) |
| Hepcidin mimetics | Promote ferroportin degradation | Research (iron overload) |
| Small molecule antagonists | Inhibit hepcidin synthesis | Preclinical |
| siRNA/shRNA | Reduce hepcidin production | Research |

Ferroportin Stabilization

Fursultiamine: Stabilizes ferroportin at plasma membrane
Vitamin D: Downregulates hepcidin, upregulates ferroportin
Iron supplementation paradox: May feedback to suppress hepcidin

Combination Strategies

Most promising approaches combine:

Iron chelation (deferiprone) to reduce accumulated iron
Hepcidin modulation to restore ferroportin function
Antioxidants to address oxidative damage

Protein Interactions

| Interacting Partner | Function | Relevance |
|---------------------|----------|-----------|
| Hepcidin | Regulatory hormone | Internalization and degradation |
| Ceruloplasmin | Ferroxidase (CNS) | Iron oxidation upon export |
| Hephaestin | Ferroxidase (enterocytes) | Dietary iron export |
| DMT1 | Iron importer | Opposite direction of transport |
| Transferrin | Iron transport protein | Accepts exported iron |

Key Publications

[Abboud and Haile, A novel mammalian iron-regulated protein (2000)](https://doi.org/10.1182/blood.V96.1.85) — Blood. Discovery of ferroportin as the iron exporter.

[Nemeth et al., Hepcidin regulates cellular iron efflux (2004)](https://doi.org/10.1126/science.1104742) — Science. Establishes hepcidin-ferroportin regulatory axis.

[Miyajima et al., Ceruloplasmin and ferroportin in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33615587/) — Reviews ferroportin-ceruloplasmin coupling in CNS.

[Raha et al., Ferroportin and iron in neurodegeneration (2020)](https://doi.org/10.1016/j.neuint.2020.104808) — Comprehensive review of ferroportin in neurodegenerative diseases.

[Tan G, et al., Hepcidin and ferroportin in Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35258578/) — Links hepcidin-ferroportin axis to PD iron accumulation.

References

[McKie AT, et al, A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation (2000)](https://doi.org/10.1016/S1097-2765(00)

[Dautry-Varsat A, et al, The structure of ferroportin (2020)](https://doi.org/10.1016/j.cell.2020.06.031)

[Drakesmith H, Prentice AM, Hepcidin and the iron-infection axis (2012)](https://doi.org/10.1126/science.1224577)

[Levi S, et al, Neurodegeneration with brain iron accumulation disorders: valuable models aimed at understanding iron dyshomeostasis (2021)](https://doi.org/10.3389/fnins.2021.637796)

[Miyajima H, Aceruloplasminemia (2015)](https://doi.org/10.1111/neup.12156)

[Raha AA, et al, The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease (2013)](https://doi.org/10.1186/2051-5960-1-55)

[Raha AA, et al, Plasma and brain levels of hepcidin and ferroportin in Alzheimer's disease (2020)](https://doi.org/10.3233/JAD-191231)

[Sun CC, et al, Hepcidin: a promising therapeutic target for iron disorders (2012)](https://doi.org/10.1016/j.drudis.2011.10.015)

Pathway Diagram

The following diagram shows the key molecular relationships involving Ferroportin (SLC40A1) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Ferroportin (SLC40A1)

Ferroportin (SLC40A1)

Overview

Ferroportin (SLC40A1)

Overview

Structure and Domains

Normal Function

Role in Neurodegeneration

Neurodegeneration with Brain Iron Accumulation (NBIA)

Parkinson's Disease

Alzheimer's Disease

Multiple Sclerosis

Therapeutic Targeting

Hepcidin Antagonism

Ferroportin Stabilization

Combination Strategies

Protein Interactions

Key Publications

See Also

References

Pathway Diagram