Ferritin Heavy Chain (FTH1)

Ferritin Heavy Chain (FTH1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ferritin Heavy Chain (FTH1)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Relationship</td>
</tr>
<tr>
<td class="label">[Ferritin Light Chain](/proteins/ferritin-l)</td>
<td>Heteropolymer</td>
</tr>
<tr>
<td class="label">[IRP1/2](/genes/ireb2)</td>
<td>Post-transcriptional regulator</td>
</tr>
<tr>
<td class="label">[Nrf2](/proteins/nrf2)</td>
<td>Transcription factor</td>
</tr>
<tr>
<td class="label">[Transferrin](/proteins/transferrin)</td>
<td>Iron uptake</td>
</tr>
<tr>
<td class="label">[Ferroportin](/genes/fpn1)</td>
<td>Iron export</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

Ferritin Heavy Chain (FTH1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Ferritin Heavy Chain (FTH1)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Relationship</td>
</tr>
<tr>
<td class="label">[Ferritin Light Chain](/proteins/ferritin-l)</td>
<td>Heteropolymer</td>
</tr>
<tr>
<td class="label">[IRP1/2](/genes/ireb2)</td>
<td>Post-transcriptional regulator</td>
</tr>
<tr>
<td class="label">[Nrf2](/proteins/nrf2)</td>
<td>Transcription factor</td>
</tr>
<tr>
<td class="label">[Transferrin](/proteins/transferrin)</td>
<td>Iron uptake</td>
</tr>
<tr>
<td class="label">[Ferroportin](/genes/fpn1)</td>
<td>Iron export</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

<div style="float: right; width: 300px; margin: 0 0 1em 1em; padding: 1em; background: #f8f9fa; border: 1px solid #ddd; border-radius: 8px; font-size: 0.9em;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">FTH1 Protein</h3>
<ul style="list-style: none; padding: 0;"> [@muhoberac2019]
<li><strong>Gene:</strong> [FTH1](/genes/fth1)</li> [@adlard2008]
<li><strong>UniProt:</strong> [P02794](https://www.uniprot.org/uniprot/P02794)</li> [@stockwell2022]
<li><strong>Molecular Weight:</strong> ~21 kDa</li>
<li><strong>Subcellular Location:</strong> Cytoplasm, nucleus, mitochondria</li>
<li><strong>PDB Structures:</strong> [2FHA](https://www.rcsb.org/structure/2FHA), [4DZ0](https://www.rcsb.org/structure/4DZ0)</li>
</ul>
</div>

Overview

Ferritin heavy chain (FTH1) is the ferroxidase component of ferritin, the primary intracellular iron storage complex. Together with ferritin light chain (FTL), FTH1 forms a 24-subunit spherical complex capable of storing up to 4,500 iron atoms. The ferroxidase activity of FTH1 converts toxic Fe2+ to Fe3+ for safe storage, playing a critical role in cellular iron homeostasis and protection against iron-mediated oxidative damage.

Structure

The ferritin complex consists of 24 subunits that self-assemble into a hollow spherical shell with 4-3-2 symmetry. FTH1 contributes ferroxidase activity through a di-iron center located in the four-helix bundle core:

• Four-helix bundle: The central structural motif containing the ferroxidase center
• Ferroxidase center: Binds two iron atoms and catalyzes Fe2+ oxidation
• Long loop: Connects helices B and C, involved in subunit interactions
• C-terminal E-helix: Contributes to inner cavity iron nucleation sites

Normal Function

Iron Storage and Detoxification

Iron-Independent Functions

• Cell proliferation: Supports rapid cell division through iron supply
• Development: Essential for embryogenesis in mice
• DNA protection: Shields nuclear DNA from iron-mediated damage
• Stress response: Upregulated by oxidative stress via Nrf2

Role in Neurodegeneration

Neurodegeneration with Brain Iron Accumulation (NBIA)

• Neuroferritinopathy: Mutations in FTL cause abnormal ferritin assembly and iron accumulation, though FTH1 is secondarily affected
• Aceruloplasminemia: Iron overload occurs despite normal ferritin, with ferritin becoming iron-saturated
• PKAN and PLA2G6: Secondary ferritin accumulation in iron-laden regions

Alzheimer's Disease

Parkinson's Disease

• Nigral ferritin reduction: Lower ferritin despite high iron
• Dopaminergic vulnerability: Low ferritin in vulnerable neurons
• [Ferroptosis](/entities/ferroptosis) susceptibility: Insufficient ferritin to handle iron load

Ferroptosis

• Iron sequestration: Prevents lipid peroxidation by reducing labile iron
• Nrf2 target: Upregulated during ferroptosis as protective response
• Therapeutic target: Ferritin induction can suppress ferroptotic cell death

Therapeutic Targeting

Iron Chelation Therapy

• Deferiprone: Can cross [BBB](/entities/blood-brain-barrier), may redistribute iron to ferritin
• Deferoxamine: Limited brain penetration
• Combined approaches: Chelation plus ferritin induction

Ferritin Induction Strategies

Biomarker Potential

• CSF ferritin: Elevated in neurodegenerative diseases
• Serum ferritin: Reflects systemic iron status
• MRI ferritin imaging: Emerging technique for brain iron assessment

Key Interactions

See Also

• [tau-protein](/proteins/tau) — Related [tau](/proteins/tau) kinase substrate in AD](/proteins)
• [amyloid-beta](/proteins/amyloid-beta-protein) — Related [APP](/entities/app-protein) cleavage product](/proteins)
• [GSK3B](/proteins/gsk3b) — Major kinase in neurodegeneration](/proteins)
• [CDK5](/genes/cdk5) — Another tau kinase](/genes)
• [BACE1](/entities/bace1) — Beta-secretase in amyloidogenesis

External Links

• [UniProt](https://www.uniprot.org/) - Protein sequence and functional data
• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [PDB](https://www.rcsb.org/) - Protein structure data

References

Pathway Diagram

The following diagram shows the key molecular relationships involving Ferritin Heavy Chain (FTH1) discovered through SciDEX knowledge graph analysis: