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Mobilization of Iron from Ferritin: New Steps and Details

Abstract

Much evidence indicates that iron stored in ferritin is mobilized through protein degradation in lysosomes, but concerns about this process have lingered, and mechanistic details of its aspects have been lacking. In the studies presented here, 59Fe-labeled ferritin was induced by preloading hepatic (HepG2) cells with radiolabeled Fe. Placing these cells in medium containing desferrioxmine resulted in loss of ferritin-59Fe, but adding high concentrations of reducing agents, or modulating internal GSH conccentrations failed to alter the rates of ferritin-59Fe release. Confocal microscopy showed that Fe deprivation increased movement of ferritin into lysosomes and hyperaccumulation when lysosomal proteolysis was inhibited. It also resulted in rapid movement of DMT1 to lysosomes, inhibited by bafilomycin. Ferrihydrite crystals isolated from purified rat liver/spleen ferritin were solubilized at pH 5 and 7 by GSH, ascorbate, citrate and lysosomal fluids obtained from liver and J774a.1 macrophages. Inhibition of DMT1/Nramp2, and siRNA knockdown of Nramp1, each reduced transfer of 59Fe from lysosomes to cytosol; and hepatocyte-specific knockout of DMT1 in mice prevented release of Fe from livers responding to EPO treatment, but did not inhibit lysosomal ferritin degradation. We conclude that ferritin-Fe mobilization does not occur through changes in cellular concentrations of reducing/chelating agents but by coordinated movement of ferritin and DMT1 to lysosomes, where the ferrihydrite crystals exposed by ferritin degradation dissolve in lysosomal fluid, and the reduced iron is transported back to the cytosol via DMT1 in hepatocytes, and by both DMT1 and Nramp1 in macrophages, prior to release into the blood or storage in ferritin.

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Publication details

The article was received on 05 Oct 2017, accepted on 28 Nov 2017 and first published on 04 Dec 2017


Article type: Paper
DOI: 10.1039/C7MT00284J
Citation: Metallomics, 2017, Accepted Manuscript
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    Mobilization of Iron from Ferritin: New Steps and Details

    A. La, T. Nguyen, K. Tran, E. Sauble, D. Tu, A. Gonzalez, T. Z. Kidane, C. Soriano, J. Morgan, M. Doan, K. Tran, C. Wang, M. D. Knutson and M. Linder, Metallomics, 2017, Accepted Manuscript , DOI: 10.1039/C7MT00284J

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