The role of NCOA4-mediated ferritinophagy in health and disease
Open accessPublished version of a preprint
Abstract
Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In iron-loaded cells, turnover of NCOA4 is greatly enhanced to block ferritin degradation and increase iron storage.
“Conversely, in iron-loaded cells the turnover of NCOA4 is greatly enhanced to block ferritin degradation and thus increase iron storage (Mancias et al., 2014, 2015; Bellelli et al., 2016; Santana-Codina and Mancias, 2018).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Santana-Codina and Mancias, 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ferroptosis: process and function
Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.158 · Cited by 3,727 · see citing works
Autophagy promotes ferroptosis by degradation of ferritin
Hou, W., Xie, Y., Song, X., Sun, X., Lotze, M. T., Zeh, H. J., Kang, R., & Tang, D. (2016) · Autophagy · doi:10.1080/15548627.2016.1187366 · Cited by 2,332 · see citing works
Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4
Scherz‐Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., & Elazar, Z. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601623 · Cited by 2,101 · see citing works
Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy
Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W., & Kimmelman, A. C. (2014) · Nature · doi:10.1038/nature13148 · Cited by 2,084 · see citing works
Self-citationYang, W. S., & Stockwell, B. R. (2008) · Chemistry & Biology · doi:10.1016/j.chembiol.2008.02.010 · Cited by 1,876 · see citing works
A Red carpet for iron metabolism
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017) · Cell · doi:10.1016/j.cell.2016.12.034 · Cited by 1,319 · see citing works
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., Rosenberg, P. A., Lo, D. C., Weinberg, J. M., Linkermann, A., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja411006a · Cited by 1,146 · cited 1× · see citing works
“Studies with genetic [70] or pharmacological inhibitors of ferroptosis [71,72] in a variety of in vitro models and multiple ND disorders (PD, AD, Huntington’s) subsequently confirmed that inhibition of ferroptosis is a potential strategy to prevent neuronal cell death.”
BackgroundMancias, J. D., Pontano Vaites, L., Nissim, S., Biancur, D. E., Kim, A. J., Wang, X., Liu, Y., Goessling, W., Kimmelman, A. C., & Harper, J. W. (2015) · eLife · doi:10.7554/elife.10308 · Cited by 552 · see citing works
Self-citationIdentification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells
Eling, N., Reuter, L., Hazin, J., Hamacher-Brady, A., & Brady, N. R. (2015) · Oncoscience · doi:10.18632/oncoscience.160 · Cited by 524 · see citing works
Louandre, C., Marcq, I., Bouhlal, H., Lachaier, E., Godin, C., Saidak, Z., François, C., Chatelain, D., Debuysscher, V., Barbare, J.-C., et al. (2015) · Cancer Letters · doi:10.1016/j.canlet.2014.11.014 · Cited by 374 · see citing works
Lazova, R., Camp, R. L., Klump, V., Siddiqui, S. F., Amaravadi, R. K., & Pawelek, J. M. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1282 · Cited by 305 · see citing works
Metabolic adaptation establishes disease tolerance to sepsis
Weis, S., Carlos, A. R., Moita, M. R., Singh, S., Blankenhaus, B., Cardoso, S., Larsen, R., Rebelo, S., Schäuble, S., Del Barrio, L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.031 · Cited by 284 · cited 1× · see citing works
“Iron is required in multiple biological processes [1] including oxygen binding and transport [2], ATP production (as a cofactor in the citric acid cycle and electron transport) [3], and DNA biosynthesis and repair [4,5].”
BackgroundDistinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells
Asano, T., Komatsu, M., Yamaguchi-Iwai, Y., Ishikawa, F., Mizushima, N., & Iwai, K. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01437-10 · Cited by 265 · see citing works
Release of iron from ferritin requires lysosomal activity
Kidane, T. Z., Sauble, E., & Linder, M. C. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00505.2005 · Cited by 263 · see citing works
NCOA4 deficiency impairs systemic iron homeostasis
Bellelli, R., Federico, G., Matte’, A., Colecchia, D., Iolascon, A., Chiariello, M., Santoro, M., De Franceschi, L., & Carlomagno, F. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.065 · Cited by 248 · see citing works
Zhang, Y., Mikhael, M., Xu, D., Li, Y., Soe-Lin, S., Ning, B., Li, W., Nie, G., Zhao, Y., & Ponka, P. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3129 · Cited by 120 · see citing works
Ferritinophagy drives uropathogenic<i>Escherichia coli</i>persistence in bladder epithelial cells
Bauckman, K. A., & Mysorekar, I. U. (2016) · Autophagy · doi:10.1080/15548627.2016.1160176 · Cited by 100 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Lipid peroxidation and ferroptosis: The role of GSH and GPx4
Ursini, F., & Maiorino, M. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.02.027 · Cited by 1,954 · see citing works
Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy
Lv, H., Zhen, C., Liu, J., Yang, P., Hu, L., & Shang, P. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3150145 · Cited by 320 · see citing works
The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
Chemistry and biology of ferritin
Plays, M., Müller, S., & Rodriguez, R. (2021) · Metallomics · doi:10.1093/mtomcs/mfab021 · Cited by 232 · see citing works
The Role of Iron in Cancer Progression
Guo, Q., Li, L., Hou, S., Yuan, Z., Li, C., Zhang, W., Zheng, L., & Li, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.778492 · Cited by 150 · see citing works
Unveiling ferroptosis as a promising therapeutic avenue for colorectal cancer and colitis treatment
Kao, A. T., Cabanlong, C. V., Padilla, K., & Xue, X. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.05.025 · Cited by 30 · see citing works
- Authors
- Santana-Codina, N., & Mancias, J. D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Mancias, Joseph D.
- Venue
- Pharmaceuticals
- Publisher
- MDPI AG
- Published
- 2018-10-23
- Volume
- 11
- Issue
- 4
- Pages
- 114
- ISSN
- 1424-8247 (ISSN-L)
- PMC
- PMC6316710
- OpenAlex
- W2896757864
- Cited by
- 410
- References
- 17
- Citations by year
- 2026: 72 · 2025: 81 · 2024: 71 · 2023: 60 · 2022: 34 · 2021: 48 · 2020: 24 · 2019: 18 · 2018: 1
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Pharmaceuticals (publishedVersion, cc-by)
- Preprints.org (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Burroughs Wellcome Fund (1014767.01)
- Claudia Adams Barr Program for Innovative Cancer Research Award (na)
- Brigham and Women’s Hospital MFCD Award (na)
- Sidney Kimmel Foundation (Kimmel Scholar Program)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- NCOA4, ferritinophagy, ferritin, iron homeostasis, ferroptosis, autophagy, erythropoiesis, heme biosynthesis, lipid peroxidation, neurodegeneration, cancer, infection, therapeutic targeting
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
