NCOA4 is a multifunctional protein that serves as a selective cargo receptor for ferritinophagy, the autophagic degradation of ferritin. This process releases iron for cellular use and is critical in neurodegenerative diseases involving iron dysregulation. [@kohan2015]
Introduction
NCOA4 (Nuclear Receptor Coactivator 4) was originally identified as a transcriptional coactivator for nuclear receptors, but has gained importance in neurodegeneration research as the key receptor mediating ferritinophagy. Iron accumulation in the brain is a hallmark of several neurodegenerative diseases, and NCOA4-mediated ferritinophagy plays a central role in iron homeostasis. [@bogdan2016]
<div class="infobox infobox-gene">
| Property | Value | |----------|-------| | Gene Symbol | NCOA4 | | Full Name | Nuclear Receptor Coactivator 4 | | Chromosomal Location | 10q11.23 | | NCBI Gene ID | 8031 | | OMIM ID | 605161 | | Ensembl ID | ENSG00000135333 | | UniProt ID | Q9UBR1 | | Encoded Protein | NCOA4 protein | | Associated Diseases | Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation |
</div>
Function
NCOA4 performs two major functions in the cell:
Transcriptional Coactivator Function
Binds to nuclear receptors including thyroid hormone receptors, retinoic acid receptors, and estrogen receptors
Enhances transcriptional activation by recruiting coactivators like CBP/p300
Regulates genes involved in metabolism, reproduction, and development
Ferritinophagy Receptor Function (Primary in Neurodegeneration)
Acts as a selective cargo receptor for [autophagy](/entities/autophagy)
Binds to ferritin (FTH1/FTL) and delivers it to autophagosomes
Critical for releasing stored iron during iron deficiency
Regulates cellular iron homeostasis through autophagic degradation
The ferritinophagy pathway is essential for:
Maintaining iron homeostasis in [neurons](/entities/neurons)
Preventing iron accumulation that leads to oxidative stress
[Ferroptosis](/mechanisms/ferroptosis) - Iron-dependent cell death pathway
[Autophagy](/mechanisms/autophagy) - NCOA4 functions in selective autophagy
[Alzheimer's disease](/diseases/alzheimers-disease) - Disease association
[Parkinson's disease](/diseases/parkinsons-disease) - Disease association
[FTH1](/genes/fth1) - Ferritin heavy chain
[FTL](/genes/ftl) - Ferritin light chain
See Also
[Neurodegeneration](/diseases/neurodegeneration) — General mechanisms
External Links
[GeneCards](https://www.genecards.org/)
[NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/)
References
[Mancias et al., Selective autophagy of ferritin is mediated by NCOA4 (2014) (2014)](https://doi.org/10.1073/pnas.1402863111)
[Dowdle et al., The selective autophagy receptor NCOA4 governs selenite-induced ferritinophagy (2014) (2014)](https://doi.org/10.1073/pnas.1405351111)
[Unknown, Bush, The role of metals in neurodegeneration and the potential for therapeutic targeting (2015) (2015)](https://doi.org/10.1016/j.neurobiolaging.2015.02.003)
[Kohan et al., The emerging role of ferritinophagy in neurodegenerative disorders (2015) (2015)](https://doi.org/10.1038/ncomms7252)
[Bogdan et al., Iron homeostasis and ferritin in neurodegeneration (2016) (2016)](https://doi.org/10.1016/j.redox.2016.03.004)
Pathway Diagram
The following diagram shows the key molecular relationships involving NCOA4 Gene discovered through SciDEX knowledge graph analysis: