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.
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These results are consistent with lysosome-mediated ferritin degradation in MEFs as previously reported.
“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]
The acidic environment of the lysosome is crucial for iron extraction from ferritin and subsequent ferritin degradation.
“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]
High levels of IRP2 are usually indicative of decreased cellular iron bioavailability.
“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]
Ferritinophagy is important for liberating iron from ferritin and for maintaining cellular iron homeostasis.
“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 primary MEFs, Dfo (50 μM) stimulated ferritin degradation substantially within 6 h.
“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]
Ferritin is selectively targeted for autophagic/lysosomal degradation by the cargo receptor NCOA4, a process required for liberating iron making it bioavailable.
“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]
Lysosomal dysfunction in senescent cells can account for ferritin and ferroportin accumulation, as both proteins are degraded through the autophagic pathway.
“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]
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- 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
- Health Sciences › Medicine › Epidemiology › 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
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