| Symbol | FPN1 |
| Full Name | Ferroportin 1 |
| Protein | [Ferroportin](/entities/ferroportin-protein) |
| Chromosome | 2q33.1 |
| NCBI Gene ID | 55730 |
| UniProt ID | Q9NP73 |
| Aliases | SLC40A1, FPN1, MTP1, IREG1, SLC11A3 |
FPN1 (Ferroportin) encodes the sole known cellular iron exporter in mammals, playing a critical role in systemic iron homeostasis and brain iron metabolism.[1] Ferroportin mediates iron efflux from cells, preventing intracellular iron accumulation that can drive oxidative damage through the Fenton reaction.[2]
The FPN1 gene spans approximately 25 kb on chromosome 2q33.1 and contains 8 exons encoding a 571-amino acid protein with 12 predicted transmembrane domains.[3] Ferroportin functions as a homodimer at the plasma membrane and is expressed in:
Ferroportin serves as the primary cellular iron exporter with the following functions:
Ferroportin is essential for maintaining brain iron balance, working in concert with transferrin receptors, DMT1, and ceruloplasmin to regulate iron trafficking across the blood-brain barrier and between neural cells.[6] Dysregulation of ferroportin expression or function contributes to pathological iron accumulation observed in neurodegenerative diseases.
In Parkinson's disease, iron accumulates in the substantia nigra where dopaminergic neurons degenerate. Ferroportin expression is reduced in PD brains, contributing to iron retention and oxidative stress.[7] Iron promotes alpha-synuclein aggregation and enhances neurotoxicity through ferroptosis.
Alzheimer's disease is characterized by iron accumulation in amyloid plaques and neurofibrillary tangles. Ferroportin co-localizes with amyloid-beta plaques, and reduced ferroportin activity may exacerbate iron-mediated oxidative damage and tau pathology.[8]
Loss-of-function mutations in FPN1 cause Neurodegeneration with Brain Iron Accumulation Type 4 (NBIA4), an autosomal dominant disorder characterized by progressive iron accumulation in the basal ganglia, cerebellum, and cerebral white matter, leading to movement disorders and cognitive decline.[9]
Hepcidin, the systemic iron regulatory hormone, binds ferroportin and induces its internalization and lysosomal degradation, thereby reducing iron export.[10] In neurodegeneration, elevated hepcidin levels (due to inflammation) may suppress ferroportin, promoting neuronal iron accumulation.
Ferroportin dysfunction contributes to ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation. Excess intracellular iron catalyzes the generation of reactive oxygen species, leading to membrane damage and cell death—a process implicated in PD, AD, and ALS.[11]
| Protein | Relationship | Function |
|---|---|---|
| HEPCIDIN | Ligand | Induces ferroportin internalization |
| Ceruloplasmin | Partner | Oxidizes Fe²⁺ to Fe³⁺ for export |
| DMT1 | Opposing | Imports iron into cells |
| Ferritin | Storage | Stores excess cellular iron |
Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annual Review of Nutrition. 2008. ↩︎
Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurology. 2014. ↩︎
Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metabolism. 2005. ↩︎
McCarthy RC, Kosman DJ. Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux. Journal of Biological Chemistry. 2013. ↩︎
Drakesmith H, Nemeth E, Ganz T. Ironing out Ferroportin. Cancer Cell. 2015. ↩︎
Moos T, Rosengren Nielsen T, Skjørringe T, Morgan EH. Iron trafficking inside the brain. Journal of Neurochemistry. 2007. ↩︎
Ayton S, Lei P, Duce JA, et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Annals of Neurology. 2013. ↩︎
Smith MA, Zhu X, Tabaton M, et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. Journal of Alzheimer's Disease. 2010. ↩︎
De Falco L, Silvestri L, Kannengiesser C, et al. Functional and clinical impact of novel ferroportin mutations. Haematologica. 2020. ↩︎
Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004. ↩︎
Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus Connecting Metabolism, Redox Biology, and Disease. Cell. 2017. ↩︎
Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxidants & Redox Signaling. 2014. ↩︎