title: Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells.
abstract: 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.
authors: Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Takeshi
authors: T
authors: Asano
authors: Masaaki
authors: M
authors: Komatsu
authors: Yuko
authors: Y
authors: Yamaguchi-Iwai
authors: Fuyuki
authors: F
authors: Ishikawa
authors: Noboru
authors: N
authors: Mizushima
authors: Kazuhiro
authors: K
authors: Iwai
mesh_terms: D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003600:Cytosol / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering
chemical_list: D034741:RNA, Small Interfering; D005293:Ferritins; D007501:Iron; D046988:Proteasome Endopeptidase Complex