The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Distinct Mechanisms of Ferritin Delivery to Lysosomes in Iron-Depleted and Iron-Replete Cells
Open accessAbstract
Ferritin is a cytosolic protein that stores excess iron, thereby protecting cells from iron toxicity. Ferritin-stored iron is believed to be utilized when cells become iron deficient; however, the mechanisms underlying the extraction of iron from ferritin have yet to be fully elucidated. Here, we demonstrate that ferritin is degraded in the lysosome under iron-depleted conditions and that the acidic environment of the lysosome is crucial for iron extraction from ferritin and utilization by cells. Ferritin was targeted for degradation in the lysosome even under iron-replete conditions in primary cells; however, the mechanisms underlying lysosomal targeting of ferritin were distinct under depleted and replete conditions. In iron-depleted cells, ferritin was targeted to the lysosome via a mechanism that involved autophagy. In contrast, lysosomal targeting of ferritin in iron-replete cells did not involve autophagy. The autophagy-independent pathway of ferritin delivery to lysosomes was deficient in several cancer-derived cells, and cancer-derived cell lines are more resistant to iron toxicity than primary cells. Collectively, these results suggest that ferritin trafficking may be differentially regulated by cell type and that loss of ferritin delivery to the lysosome under iron-replete conditions may be related to oncogenic cellular transformation.
Overview
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
Verification
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 the citing paper
“These results are consistent with lysosome-mediated ferritin degradation in MEFs as previously reported [51], [54], [55].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
In the citing paper
“The acidic environment of the lysosome is crucial for iron extraction from ferritin and for subsequent ferritin degradation [51].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
In the citing paper
“Therefore, high levels of IRP2 are usually indicative of decreased cellular iron bioavailability.”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
In the citing paper
“Ferritinophagy, the process of ferritin being sequestered into autophagosomes and delivered to lysosomes for degradation, is important for liberating iron from ferritin and thus for maintaining cellular iron homeostasis [51], [53], [54], [55].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
In the citing paper
“Ferritin degradation was then stimulated with the iron chelator deferoxamine (Dfo) (50 µM) as previously described [51], [53], [56] and occurred substantially within 6 h of treatment (Fig. 5A(i)).”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
In the citing paper
“Ferritin is selectively targeted for autophagic/lysosomal degradation by the cargo receptor NCOA4 [53], a process required for liberating iron making it bioavailable to the cell [51], [53], [65].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
In the citing paper
“Nonetheless, lysosomal dysfunction in senescent cells can account for ferritin and ferroportin accumulation, as both proteins are degraded through the autophagic pathway [51], [89].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [51]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351
Cui, C., Cui, J., Jin, F., Cui, Y., Li, R., Jiang, X., Tian, Y., Wang, R. C., Jiang, P., & Gao, J. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479571 · Cited by 5,214
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497
Autophagy: process and functionPreprint
Mizushima, N. (2007) · Genes & Development · doi:10.1101/gad.1599207 · Cited by 4,104
The role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865
Self-citationThe ferritins: molecular properties, iron storage function and cellular regulation
Harrison, P. M., & Arosio, P. (1996) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(96)00022-9 · Cited by 2,667
Impairment of starvation-induced and constitutive autophagy in Atg7 -deficient mice
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412022 · Cited by 2,331
Self-citationCepharanthine potently enhances the sensitivity of anticancer agents in K562 cells
Ikeda, R., Che, X., Yamaguchi, T., Ushiyama, M., Zheng, C., Okumura, H., Takeda, Y., Shibayama, Y., Nakamura, K. T., Jeung, H., et al. (2005) · Cancer Science · doi:10.1111/j.1349-7006.2005.00057.x · Cited by 2,268
Eaten alive: a history of macroautophagy
Yang, Z., & Klionsky, D. J. (2010) · Nature Cell Biology · doi:10.1038/ncb0910-814 · Cited by 2,155
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
Komatsu, M., Waguri, S., Koike, M., Sou, Y.-S., Ueno, T., Hara, T., Mizushima, N., Iwata, J.-I., Ezaki, J., Murata, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.035 · Cited by 2,124
Two to tango: Regulation of Mammalian iron metabolism
Hentze, M. W., Muckenthaler, M. U., Galy, B., & Camaschella, C. (2010) · Cell · doi:10.1016/j.cell.2010.06.028 · Cited by 2,120
Hentze, M. W., Muckenthaler, M. U., & Andrews, N. C. (2004) · Cell · doi:10.1016/s0092-8674(04)00343-5 · Cited by 1,736
Yoshimori, T., Yamamoto, A., Moriyama, Y., Futai, M., & Tashiro, Y. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)47429-2 · Cited by 1,334
Chen, Z., Hagler, J., Palombella, V. J., Melandri, F. D., Scherer, D. C., Ballard, D. W., & Maniatis, T. (1995) · Genes & Development · doi:10.1101/gad.9.13.1586 · Cited by 1,270
Regulating the fate of mRNA: the control of cellular iron metabolism
Klausner, R. D., Rouault, T. A., & Harford, J. B. (1993) · Cell · doi:10.1016/0092-8674(93)90046-s · Cited by 1,210
pH and the recycling of transferrin during receptor-mediated endocytosis.
Dautry‐Varsat, A., Ciechanover, A. J., & Lodish, H. F. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.8.2258 · Cited by 1,178
Regulation of ferritin genes and protein
Torti, F. M., & Torti, S. V. (2002) · Blood · doi:10.1182/blood.v99.10.3505 · Cited by 1,173
A Role for NBR1 in Autophagosomal Degradation of Ubiquitinated Substrates
Kirkin, V., Lamark, T., Sou, Y.-S., Bjørkøy, G., Nunn, J. L., Bruun, J.-A., Shvets, E., McEwan, D. G., Clausen, T. H., Wild, P., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.01.020 · Cited by 1,065
The role of iron regulatory proteins in mammalian iron homeostasis and disease
Rouault, T. A. (2006) · Nature Chemical Biology · doi:10.1038/nchembio807 · Cited by 1,055
Ferritins: A family of molecules for iron storage, antioxidation and more
Arosio, P., Ingrassia, R., & Cavadini, P. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.09.004 · Cited by 886
Ohgami, R. S., Campagna, D. R., Greer, E. L., Antiochos, B., McDonald, A., Chen, J., Sharp, J. J., Fujiwara, Y., Barker, J. E., & Fleming, M. D. (2005) · Nature Genetics · doi:10.1038/ng1658 · Cited by 775
The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel
Dong, X., Cheng, X., Mills, E., Delling, M., Wang, F., Kurz, T., & Xu, H. (2008) · Nature · doi:10.1038/nature07311 · Cited by 588
Consequences of the selective blockage of chaperone-mediated autophagy
Massey, A. C., Kaushik, S., Sovak, G., Kiffin, R., & Cuervo, A. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507436103 · Cited by 529
Ferritins: Dynamic Management of Biological Iron and Oxygen Chemistry
Liu, X., & Theil, E. C. (2005) · Accounts of Chemical Research · doi:10.1021/ar0302336 · Cited by 514
Autophagy: Many paths to the same end
Cuervo, A. M. (2004) · Molecular and Cellular Biochemistry · doi:10.1023/b:mcbi.0000041848.57020.57 · Cited by 493
Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex
Bao, G., Clifton, M., Hoette, T. M., Mori, K., Deng, S.-X., Qiu, A., Viltard, M., Williams, D., Paragas, N., Leete, T., et al. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.402 · Cited by 307
Devireddy, L. R., Hart, D. O., Goetz, D. H., & Green, M. R. (2010) · Cell · doi:10.1016/j.cell.2010.04.040 · Cited by 295
Iwai, K., Drake, S. K., Wehr, N. B., Weissman, A. M., LaVaute, T., Minato, N., Klausner, R. D., Levine, R. L., & Rouault, T. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4924 · Cited by 293
Lysosomes and oxidative stress in aging and apoptosis
Kurz, T., Terman, A., Gustafsson, B., & Brunk, U. T. (2008) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.01.009 · Cited by 287
Molecular control of vertebrate iron homeostasis by iron regulatory proteins
Wallander, M. L., Leibold, E. A., & Eisenstein, R. S. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.05.004 · Cited by 287
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 · cited 2×
“Several groups have reported that lysosomal degradation of ferritin is crucial for the utilization of ferritin iron stores in a number of different settings (25, 33, 42) and plays a central role in iron extraction from ferritin.”
BackgroundChaperone-mediated autophagy: selectivity pays off
Cuervo, A. M. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.10.003 · Cited by 260 · cited 7×
“CMA is not involved in ferritin degradation by knocking down Lamp2A in MEFs, which is consistent with the observation that ferritin delivery to the lysosome in iron-replete MEFs was inhibited by 3-MA, since CMA is insensitive to 3-MA (17).”
BackgroundInfluentialFerroportin‐mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome
De Domenico, I., Vaughn, M. B., Li, L., Bagley, D., Musci, G., Ward, D. M., & Kaplan, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601409 · Cited by 235
Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2
Iwai, K., Klausner, R. D., & Rouault, T. A. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00219.x · Cited by 211
Specific iron chelators determine the route of ferritin degradation
De Domenico, I., Ward, D. M., & Kaplan, J. (2009) · Blood · doi:10.1182/blood-2009-05-224188 · Cited by 176
Iron in cytosolic ferritin can be recycled through lysosomal degradation in human fibroblasts
Radisky, D. C., & Kaplan, J. (1998) · Biochemical Journal · doi:10.1042/bj3360201 · Cited by 163
Iron Metabolism: From Molecular Mechanisms to Clinical Consequences
Crichton, R. R. (2009) · Cited by 159
Effects of Small Molecules on Chaperone-Mediated Autophagy
Finn, P. F., Mesires, N. T., Vine, M., & Dice, J. F. (2005) · Autophagy · doi:10.4161/auto.1.3.2000 · Cited by 153
Lauffer, R. B. (2018) · CRC Press eBooks · doi:10.1201/9781351073899 · Cited by 152
Localized Unfolding at the Junction of Three Ferritin Subunits
Takagi, H., Shi, D., Ha, Y., Allewell, N. M., & Theil, E. C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.30.18685 · Cited by 130
Ferritin. Uptake, storage, and release of iron.
Chasteen, N. D. (1998) · PubMed · Cited by 119
Crichton, R. R. (2009) · Wiley eBooks · doi:10.1002/9780470010303 · Cited by 111
Molecular control of iron metabolism
Andrews, N. C. (2005) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2004.10.004 · Cited by 109
Jin, W., Takagi, H., Pancorbo, B., & Theil, E. C. (2001) · Biochemistry · doi:10.1021/bi002509c · Cited by 98
Uptake—Microautophagy—and degradation of exogenous proteins by isolated rat liver lysosomes
Ahlberg, J., & Glaumann, H. (1985) · Experimental and Molecular Pathology · doi:10.1016/0014-4800(85)90020-6 · Cited by 88
Larson, J. A., Howie, H. L., & So, M. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04169.x · Cited by 85
Kwok, J., & Richardson, D. R. (2004) · Molecular Pharmacology · doi:10.1124/mol.65.1.181 · Cited by 71
Ashizuka, M., Fukuda, T., Nakamura, T., Shirasuna, K., Iwaï, K., Izumi, H., Kohno, K., Kuwano, M., & Uchiumi, T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.18.6375-6383.2002 · Cited by 63
Iron Prevents Ferritin Turnover in Hepatic Cells
Truty, J., Malpe, R., & Linder, M. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105392200 · Cited by 49
Siderosomal ferritin. The missing link between ferritin and haemosiderin?
Andrews, S. C., Treffry, A., & Harrison, P. M. (1987) · Biochemical Journal · doi:10.1042/bj2450439 · Cited by 42
Solubility of colloidal ferric hydroxide
Fox, L. E. (1988) · Nature · doi:10.1038/333442a0 · Cited by 26
A ferrireductase fills the gap in the transferrin cycle
McKie, A. T. (2005) · Nature Genetics · doi:10.1038/ng1105-1159 · Cited by 22
Cited by
Sorted by citations
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,897
Self-citationQuantitative 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
Cargo recognition and degradation by selective autophagy
Gatica, D., Lahiri, V., & Klionsky, D. J. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0037-z · Cited by 1,067
Oxidative Stress in Aging Human Skin
Rinnerthaler, M., Bischof, J., Streubel, M., Trost, A., & Richter, K. (2015) · Biomolecules · doi:10.3390/biom5020545 · Cited by 1,053
Metadata
- Authors
- Asano, T., Komatsu, M., Yamaguchi-Iwai, Y., Ishikawa, F., Mizushima, N., & Iwai, K.
- Affiliations
- Kyoto University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Department of Applied Molecular Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8503, Japan
- Tokyo Medical and Dental University (JP)
- Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2011-05-01
- Volume
- 31
- Issue
- 10
- Pages
- 2040-2052
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3133360
- OpenAlex
- W2112800403
- Cited by
- 265
- References
- 53
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 24 · 2023: 27 · 2022: 20 · 2021: 28 · 2020: 17 · 2019: 20 · 2018: 16 · 2017: 18 · 2016: 20 · 2015: 13 · 2014: 13 · 2013: 6 · 2012: 5
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- ferritin, lysosomal degradation, iron extraction, iron storage, iron deficiency, autophagy, lysosomal targeting, low pH, cancer cells, oncogenic transformation, protein trafficking
- MeSH terms
- Iron Deficiencies, Animals, Autophagy, Cell Transformation, Neoplastic, Cytosol, Ferritins, Fluorescent Antibody Technique, HeLa Cells, Homeostasis, Humans, Hydrogen-Ion Concentration, Iron, Lysosomes, Mice, Inbred C57BL, Neoplasms, Immunoblotting, RNA, Small Interfering, Cell Line, Tumor, Proteasome Endopeptidase Complex, Mice, Gene Knockout Techniques
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
