Ferroportin is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Ferroportin (also known as SLC40A1, IREG1, or MTP1) is the sole known cellular iron exporter in mammals and plays a central role in systemic iron homeostasis. This transmembrane protein is essential for dietary iron absorption, iron recycling from macrophages, and iron transport across the blood-brain barrier.
Ferroportin is a 571-amino acid protein with 12 transmembrane domains. The protein forms homodimers and functions as a facilitated transporter, moving ferrous iron (Fe²⁺) across cell membranes in a pH- and temperature-dependent manner[1]. Recent cryo-EM structures reveal an inward-open conformation that undergoes conformational changes upon hepcidin binding[2].
Ferroportin exports Fe²⁺ from cells using a concentration gradient. The export mechanism involves[3]:
Ferroportin is the primary target of hepcidin, the master iron-regulatory hormone[4]:
Ferroportin is expressed on brain endothelial cells and mediates iron efflux from the brain[5]. Dysregulation leads to:
Ferroportin dysfunction contributes to ferroptosis, an iron-dependent cell death pathway[6]:
In Parkinson's disease, ferroportin expression is decreased in dopaminergic neurons[7]:
In Alzheimer's disease, ferroportin dysfunction contributes to pathology[8]:
Aceruloplasminemia demonstrates the critical ferroportin-ceruloplasmin relationship[9]:
The SLC40A1 gene encodes ferroportin and is located on chromosome 2q32.2[10]. Mutations cause:
SLC40A1 polymorphisms have been associated with[11]:
Ferroportin upregulation is a potential therapeutic strategy[12]:
Targeting the hepcidin-ferroportin axis offers therapeutic potential[13]:
Ferroportin levels may serve as a biomarker[14]:
| Protein | Interaction | Functional Outcome |
|---|---|---|
| Hepcidin | Binds and induces degradation | Iron export inhibition |
| Ceruloplasmin | Ferroxidase activity | Fe²⁺ to Fe³⁺ conversion |
| Transferrin | Iron acceptor | Iron transport in plasma |
| DMT1 | Complementary iron transport | Iron import |
| Ferritin | Storage relationship | Iron buffering |
Current research focuses on[15]:
McKie AT et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Molecular Cell. 2000. ↩︎
Taniguchi R et al. Cryoo-EM structures of human ferroportin in its inward-open and hepcidin-bound states. Nature Communications. 2023. ↩︎
Ward DM, Kaplan J. Ferroportin-mediated iron transport: expression and regulation. Biochimica et Biophysica Acta. 2012. ↩︎
Nemeth E et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004. ↩︎
Rouault TA. Iron metabolism in the central nervous system and neurodegenerative disorders. Current Opinion in Neurobiology. 2013. ↩︎
Stockwell BR et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017. ↩︎
Ayton S et al. Ferroportin in the substantia nigra in Parkinson's disease. Neurobiology of Aging. 2013. ↩︎
Raha AA et al. The blood-brain barrier in Alzheimer's disease: therapeutic potential of ferroportin. Cells. 2023. ↩︎
Miyajima H. Aceruloplasminemia. Neuropathology. 2015. ↩︎
Pietrangelo A. The ferroportin disease. Blood Cells, Molecules, and Diseases. 2004. ↩︎
Nandar W, Connor JR. Ferroportin and iron regulation in neurodegeneration. Neurobiology of Disease. 2019. ↩︎
Devos D et al. Targeting brain iron in Parkinson's disease with deferiprone. Movement Disorders. 2019. ↩︎
Zhou Y et al. Hepcidin-ferroportin axis in neurodegenerative disorders. Oxidative Medicine and Cellular Longevity. 2022. ↩︎
Baik HW et al. Serum ferroportin as a potential biomarker for Parkinson's disease. Scientific Reports. 2022. ↩︎
Gao G, Li J, Zhang Y, Chang YZ. Cellular iron metabolism and ferroptosis in neurodegeneration. Neural Regeneration Research. 2023. ↩︎