A possible role for secreted ferritin in tissue iron distribution

Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, 32000, Technion City, Haifa, Israel.
Journal of Neural Transmission (Impact Factor: 2.4). 02/2011; 118(3):337-47. DOI: 10.1007/s00702-011-0582-0
Source: PubMed


Ferritin is known as a well-conserved iron detoxification and storage protein that is found in the cytosol of many prokaryotic and eukaryotic organisms. In insects and worms, ferritin has evolved into a classically secreted protein that transports iron systemically. Mammalian ferritins are found intracellularly in the cytosol, as well as in the nucleus, the endo-lysosomal compartment and the mitochondria. Extracellular ferritin is found in fluids such as serum and synovial and cerebrospinal fluids. We recently characterized the biophysical properties, secretion mechanism and cellular origin of mouse serum ferritin, which is actively secreted by a non-classical pathway involving lysosomal processing. Here, we review the data to support a hypothesis that intracellular and extracellular ferritin may play a role in intra- and intercellular redistribution of iron.

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    • "An unusual property of ferritin is the existence of functional forms in both cytoplasmic and extracellular environments [6]. In contrast to cytoplasmic ferritins which widely exist in both vertebrates and invertebrates, secreted ferritins are mainly found in insects and worms [7]. They generally function as a major iron storage/transport molecule. "
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    ABSTRACT: As an important iron storage protein, ferritin plays a crucial role in the iron-withholding defense system. In this study, two secreted ferritin subunits (PyFerS1 and PyFerS2) were identified from the Yesso scallop, Patinopecten yessoensis. The complete DNA sequences of the two ferritins are 7101 and 5359 bp, consisting of seven and five exons, respectively. The full-length cDNAs of PyFerS1 and PyFerS2 are 960 and 956 bp in length, encoding 228 and 220 amino acids, respectively. They have typical ferritin structures, with four long α-helices, one short α-helix and an L-loop. Signal peptides were found at the N-terminus of both ferritins, and phylogenetic analysis showed that they both clustered with secreted mollusc ferritins. PyFerS1 possesses all seven conserved residues of the ferroxidase center, whereas PyFerS2 only has two. Real-time PCR analysis indicated high expression level of PyFerS2 in the D-shaped larvae, and PyFerS1 in both D-shaped larvae and fertilized eggs. In adult scallops, PyFerS1 was only detected in the hepatopancreas, whereas PyFerS2 was detected in both hepatopancreas and mantle. After the scallops were challenged by iron ion or bacteria Vibrio anguillarum, the expression of both PyFerS1 and PyFerS2 was significantly elevated, suggesting they may play a role in scallop innate immune defense. For the first time, secreted ferritins were cloned and comprehensively characterized in bivalve molluscs. It will assist in better understanding of the role of secreted ferritins in bivalve innate immunity.
    Full-text · Article · Jan 2014 · Fish & Shellfish Immunology
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    • "Both subunits are highly conserved [25], nevertheless, genetically separated [26, 27], and maintain distinct functions [28]. Several observations reported that ferritin subunits (FTH and FTL) are iron storage proteins and their amount could only be modified by changes in iron status [40–42]. However, others and we reported that change in ferritin-subunits is not only due to the increase in hepatic iron concentration, but it could also be due to the direct effect of different inflammatory mediators such as acute-phase cytokines [33, 43–45]. "
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    ABSTRACT: The current study aimed to investigate radiation-induced regulation of iron proteins including ferritin subunits in rats. Rat livers were selectively irradiated in vivo at 25 Gy. This dose can be used to model radiation effects to the liver without inducing overt radiation-induced liver disease. Sham-irradiated rats served as controls. Isolated hepatocytes were irradiated at 8 Gy. Ferritin light polypeptide (FTL) was detectable in the serum of sham-irradiated rats with an increase after irradiation. Liver irradiation increased hepatic protein expression of both ferritin subunits. A rather early increase (3 h) was observed for hepatic TfR1 and Fpn-1 followed by a decrease at 12 h. The increase in TfR2 persisted over the observed time. Parallel to the elevation of AST levels, a significant increase (24 h) in hepatic iron content was measured. Complete blood count analysis showed a significant decrease in leukocyte number with an early increase in neutrophil granulocytes and a decrease in lymphocytes. In vitro, a significant increase in ferritin subunits at mRNA level was detected after irradiation which was further induced with a combination treatment of irradiation and acute phase cytokine. Irradiation can directly alter the expression of ferritin subunits and this response can be strongly influenced by radiation-induced proinflammatory cytokines. FTL can be used as a serum marker for early phase radiation-induced liver damage.
    Full-text · Article · Dec 2013
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    • "In insects and worms, ferritin belongs to classically secreted proteins that transport iron. Intracellular and extracellular ferritin may play a role in intra-and intercellular redistribution of iron (Meyron-Holtz et al., 2011). "
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    ABSTRACT: Ferritin, an iron storage protein, is present in the serum and cerebrospinal fluid, has receptors on the cell surface, able to penetrate the brain-blood barrier, can be secreted from the cells, and leaks from destroyed cell in insult and brain trauma. The effect of exogenous ferritin on the key characteristic of glutamatergic neurotransmission was assessed in rat brain nerve terminals (synaptosomes). Exogenous ferritin (80μg/ml, iron content 0.7 %) significantly increased the ambient level of L-[(14)C]glutamate (0.200±0.015 versus 0.368±0.016nmol/mg of protein) and endogenous glutamate (fluorimetric glutamate dehydrogenase assay) in the nerve terminals. This increase was not a result of augmentation of tonic release because the velocity of tonic release of L-[(14)C]glutamate was not changed significantly in ferritin-treated synaptosomes as compared to the control. Ferritin caused a decrease in synaptic vesicle acidification that was shown using fluorescent dye acridine orange. Iron-dependence of the effects of ferritin was analyzed with apoferritin (0.0025 % residual iron). Apoferritin weakly affected the proton electrochemical gradient of synaptic vesicles but increased the ambient level and decreased the initial velocity of uptake of L-[(14)C]glutamate by synaptosomes, nevertheless these effects were ~30 % lesser than those caused by ferritin. Exogenous ferritin can provoke the development of excitotoxicity increasing the ambient level of glutamate and lowering synaptic vesicle acidification and glutamate uptake in the nerve terminals, however these effects are not completely iron-dependent. Thus, in the CNS exogenous ferritin can act as modulator of glutamate homeostasis in iron-dependent and iron-independent manner.
    Full-text · Article · Dec 2013 · Molecular and Cellular Neuroscience
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