[^1]
- Gene: [AIFM2](/genes/aifm2)
[^2]
- Aliases: FSP1, AMID, PRG3
[^3]
- UniProt: [Q9BRQ8](https://www.uniprot.org/uniprot/Q9BRQ8)
- Molecular Weight: ~37 kDa
- Subcellular Location: Plasma membrane, mitochondria, lipid droplets
- PDB Structures: [2JMD](https://www.rcsb.org/structure/2JMD)
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.
FSP1 shares homology with 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.
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 reactions
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
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
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
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
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
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
Motor neuron vulnerability:
- SOD1 mutations: Increase oxidative stress
- Iron accumulation: Found in motor cortex
- Ferroptosis markers: Elevated in patient tissue
- FSP1 upregulation: May be compensatory
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 transcription
Supporting the FSP1-CoQ10 axis:
- Ubiquinol supplements: Direct antioxidant provision
- Mitochondrial-targeted CoQ10: MitoQ, SkQ1
- Brain-penetrant formulations: Improve bioavailability
Multi-target approaches:
- GPX4 + FSP1 activation: Dual pathway protection
- Iron chelation + FSP1: Reduce iron and boost antioxidant
- Vitamin E + FSP1: Synergistic membrane protection
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
| Interactor |
Relationship |
Functional Relevance |
| Coenzyme Q10 |
Substrate |
FSP1 reduces CoQ10 to ubiquinol |
| GPX4 |
Parallel pathway |
Independent ferroptosis suppression |
| NAD(P)H |
Cofactor |
Electron donor for reduction |
| Vitamin E |
Regeneration target |
FSP1 reduces oxidized vitamin E |
| p53 |
Transcriptional regulator |
Induces FSP1 expression |
- UniProt - Protein sequence and functional data
- PubMed - Biomedical literature
- PDB - Protein structure data