FSP1/AIFM2 (Ferroptosis Suppressor Protein 1)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">FSP1/AIFM2 (Ferroptosis Suppressor Protein 1)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Relationship</td>
</tr>
<tr>
<td class="label">Coenzyme Q10</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">[GPX4](/proteins/gpx4-protein)</td>
<td>Parallel pathway</td>
</tr>
<tr>
<td class="label">NAD(P)H</td>
<td>Cofactor</td>
</tr>
<tr>
<td class="label">Vitamin E</td>
<td>Regeneration target</td>
</tr>
<tr>
<td class="label">p53</td>
<td>Transcriptional regulator</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/chronic-kidney-disease" style="color:#ef9a9a">Chronic Kidney Disease</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">129 edges</a></td>
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<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">FSP1 Protein</h3>
<ul style="list-style: none; padding: 0;"> [@stockwell2022]
<li><strong>Gene:</strong> [AIFM2](/genes/aifm2)</li> [@do2021]
<li><strong>Aliases:</strong> FSP1, AMID, PRG3</li> [@mishima2022]
<li><strong>UniProt:</strong> [Q9BRQ8](https://www.uniprot.org/uniprot/Q9BRQ8)</li>
<li><strong>Molecular Weight:</strong> ~37 kDa</li>
<li><strong>Subcellular Location:</strong> Plasma membrane, mitochondria, lipid droplets</li>
<li><strong>PDB Structures:</strong> [2JMD](https://www.rcsb.org/structure/2JMD)</li>
</ul>
</div>
Overview
Mermaid diagram (expand to render)
[Ferroptosis](/entities/ferroptosis) suppressor protein 1 (FSP1, also known as AIFM2) is a NAD(P)H-dependent oxidoreductase that protects cells from ferroptosis by generating reduced coenzyme Q10 (ubiquinol) in the plasma membrane. Discovered in 2019 as a potent ferroptosis suppressor, FSP1 acts independently of the canonical GPX4 pathway to prevent lipid peroxidation and maintain membrane integrity.
Structure
FSP1 shares homology with [apoptosis](/entities/apoptosis)-inducing factor (AIF) but has distinct functional properties:
- FAD-binding domain: Binds flavin adenine dinucleotide cofactor
- NAD(P)H-binding site: Electron donor binding
- Myristoylation site: N-terminal glycine for membrane targeting
- Transmembrane region: Associates with plasma membrane
- Nuclear localization signals: Can shuttle to nucleus
The myristoylation at Gly2 is essential for plasma membrane localization and ferroptosis suppression activity.
Normal Function
Coenzyme Q10 Reduction
FSP1 catalyzes the reduction of oxidized coenzyme Q10:
CoQ10 (oxidized) + NAD(P)H -> CoQ10H2 (ubiquinol) + NAD(P)+
This generates a membrane-localized antioxidant pool that:
Traps lipid peroxyl radicals: Direct radical-scavenging
Regenerates vitamin E: Reduces oxidized alpha-tocopherol
Maintains membrane integrity: Prevents lipid peroxidation chain reactionsRedundant Ferroptosis Defense
FSP1 provides backup protection alongside GPX4:
- Parallel pathway: Functions when GPX4 is inhibited
- Synergistic protection: Combined loss is lethal
- Context-dependent: Importance varies by cell type
Other Functions
FSP1 has additional roles beyond ferroptosis:
- DNA damage response: Induced by p53
- Metabolic regulation: NAD(P)H-dependent metabolism
- Cell death regulation: Can promote apoptosis in some contexts
Role in Neurodegeneration
Ferroptosis in Neurodegeneration
FSP1's role in preventing ferroptosis is highly relevant to neurodegeneration:
High iron content: Brain regions vulnerable to ferroptosis
Polyunsaturated fatty acids: Neuronal membranes rich in PUFA
Low antioxidant capacity: Limited GPX4 in some [neurons](/entities/neurons)Alzheimer's Disease
FSP1 alterations in AD:
- Iron accumulation: Hippocampal and cortical iron deposits
- Lipid peroxidation: Elevated 4-HNE and MDA
- CoQ10 depletion: Reduced antioxidant capacity
- Therapeutic potential: FSP1 upregulation may protect
Parkinson's Disease
Dopaminergic neuron vulnerability relates to ferroptosis:
- Nigral iron accumulation: Promotes lipid peroxidation
- Dopamine oxidation: Generates reactive species
- GPX4 sensitivity: Dopaminergic neurons depend on GPX4
- FSP1 protective role: Potential therapeutic target
Huntington's Disease
Ferroptosis involvement in HD:
- Mitochondrial dysfunction: Increases oxidative stress
- Iron dysregulation: Abnormal iron handling
- Lipid metabolism: Altered PUFA metabolism
- Cell death mechanism: Ferroptosis contributes to striatal loss
ALS/FTD
Motor neuron vulnerability:
- SOD1 mutations: Increase oxidative stress
- Iron accumulation: Found in motor [cortex](/brain-regions/cortex)
- Ferroptosis markers: Elevated in patient tissue
- FSP1 upregulation: May be compensatory
Therapeutic Targeting
FSP1 Induction
Strategies to boost FSP1 activity:
Gene therapy: AAV-FSP1 delivery to brain
Small molecule inducers: Compounds that increase FSP1 expression
Upstream pathway modulation: Target regulators of FSP1 transcriptionCoQ10 Supplementation
Supporting the FSP1-CoQ10 axis:
- Ubiquinol supplements: Direct antioxidant provision
- Mitochondrial-targeted CoQ10: MitoQ, SkQ1
- Brain-penetrant formulations: Improve bioavailability
Combination Therapies
Multi-target approaches:
- GPX4 + FSP1 activation: Dual pathway protection
- Iron chelation + FSP1: Reduce iron and boost antioxidant
- Vitamin E + FSP1: Synergistic membrane protection
Cancer Applications
FSP1 as a cancer target (opposite of neurodegeneration):
- FSP1 inhibitors: Sensitize tumors to ferroptosis
- GPX4 inhibitors: Combined blockade kills cancer cells
- Selective targeting: Spare neurons while killing tumor cells
Key Interactions
See Also
- [tau-protein](/proteins/tau) — Related [tau](/proteins/tau) kinase substrate in AD
- [amyloid-beta](/proteins/amyloid-beta-protein) — Related [APP](/entities/app-protein) cleavage product
- [GSK3B](/proteins/gsk3b) — Major kinase in neurodegeneration
- [CDK5](/genes/cdk5) — Another tau kinase
- [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
[Doll et al., FSP1 is a glutathione-independent ferroptosis suppressor (2019) (2019)](https://doi.org/10.1038/s41586-019-1707-0)
[Bersuker et al., The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis (2019) (2019)](https://doi.org/10.1038/s41586-019-1705-2)
[Unknown, Stockwell, Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications (2022) (2022)](https://doi.org/10.1016/j.cell.2022.06.003)
[Do Van et al., Ferroptosis, a newly characterized form of cell death in Parkinson's disease (2021) (2021)](https://doi.org/10.1016/j.neurobioldis.2021.105391)
[Mishima et al., HPLC-based assay for FSP1-mediated ferroptosis suppression (2022) (2022)](https://doi.org/10.1016/j.chembiol.2022.02.006)Pathway Diagram
The following diagram shows the key molecular relationships involving FSP1/AIFM2 (Ferroptosis Suppressor Protein 1) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)