Ferritin is considered the major iron storage protein which maintains a large iron core in its cavity and has ferroxidase activity. There are many types of ferritin particularly in prokaryotes that include the canonical 24-mer FTN molecules, the heme-containing BFR, the smaller 12-mer DPS and the newly recognized EncFtn of encapsulin that forms a very large iron storage compartment. Recent studies show that ferritin function is more dynamic than previous depicted and new mechanisms of ferritin iron recycling are emerging. They participate to the regulation of cellular iron homeostasis as those of ferritin biosynthesis, cooperating also with the iron-dependent mechanism of cellular iron secretion. Some of these basic processes are in common between unicellular and animal cells, and this review aims at discussing the findings on the connections between iron storage, cellular iron regulation and ferritin iron recycling that have been explored in unicellular organisms and in animals. © 2017 IUBMB Life, 69(6):414-422, 2017.

Disease tolerance is a defense strategy that limits the fitness costs of infection irrespectively of pathogen burden. While restricting iron (Fe) availability to pathogens is perceived as a host defense strategy, the resulting tissue Fe overload can be cytotoxic and promote tissue damage to exacerbate disease severity. Examining this interplay during malaria, the disease caused by Plasmodium infection, we find that expression of the Fe sequestering protein ferritin H chain (FtH) in mice, and ferritin in humans, is associated with reduced tissue damage irrespectively of pathogen burden. FtH protection relies on its ferroxidase activity, which prevents labile Fe from sustaining proapoptotic c-Jun N-terminal kinase (JNK) activation. FtH expression is inhibited by JNK activation, promoting tissue Fe overload, tissue damage, and malaria severity. Mimicking FtH's antioxidant effect or inhibiting JNK activation pharmacologically confers therapeutic tolerance to malaria in mice. Thus, FtH provides metabolic adaptation to tissue Fe overload, conferring tolerance to malaria.

Hepcidin is a major regulator of iron homeostasis, and its expression in liver is regulated by iron, inflammation, and erythropoietic activity with mechanisms that involve bone morphogenetic proteins (BMPs) binding their receptors and coreceptors. Here we show that exogenous heparin strongly inhibited hepcidin expression in hepatic HepG2 cells at pharmacologic concentrations, with a mechanism that probably involves bone morphogenetic protein 6 sequestering and the blocking of SMAD signaling. Treatment of mice with pharmacologic doses of heparin inhibited liver hepcidin mRNA expression and SMAD phosphorylation, reduced spleen iron concentration, and increased serum iron. Moreover, we observed a strong reduction of serum hepcidin in 5 patients treated with heparin to prevent deep vein thrombosis, which was accompanied by an increase of serum iron and a reduction of C-reactive protein levels. The data show an unrecognized role for heparin in regulating iron homeostasis and indicate novel approaches to the treatment of ironrestricted iron deficiency anemia. IntroductionIron maldistribution is implicated in various diseases, including hemochromatosis, iron-loading anemias, anemia of inflammation, and neurodegenerative disorders. 1 Body iron absorption and distribution are controlled by hepcidin, a small peptide secreted by hepatocytes that is expressed as a prepropeptide of 84 amino acids and is processed to the mature hormone of 25 residues by furin. 2,3 Hepcidin binds and induces the degradation of ferroportin, the only known cellular iron exporter, and thus it regulates iron absorption from duodenum and iron release from reticuloendothelial macrophages. 4 Inappropriately low levels of hepcidin are associated with the various forms of genetic hemochromatosis, 5 whereas high levels of hepcidin are found in inflammatory conditions, where they contribute to anemia. 6 Liver hepcidin expression is regulated by iron, erythropoietic activity, and inflammation, 6 with mechanisms that strongly rely on bone morphogenetic protein (BMP) signaling pathways. 7 Hemojuvelin, which is a main hepcidin regulator, acts as a BMP coreceptor, 8 and the modulation of its level by proteases tightly regulates hepcidin expression. 9,10 Hepcidin expression in hepatic cells is strongly stimulated by BMP2, BMP4, BMP6, and BMP9 11 and is reduced by inhibitors of the BMP/SMAD signaling pathway, such as noggin or dorsomorphin. 12 BMP6 is considered the physiologic BMP regulator of hepcidin because its expression is iron dependent and because BMP6 knockout mice demonstrate massive liver iron overload. 13,14 Hepcidin also is stimulated by the inflammatory cytokine interleukin-6 (IL-6) in a pathway that involves signal transducer and activator of transcription 3 (STAT3), [15][16][17] but it is dependent on the presence of SMAD4. 18 Methods to control hepcidin expression can be based on the modulation of BMP's activity. These proteins belong to the transforming growth factor-␤ family and exhibit a wide range of biologic effects on various cell types....

X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by defects of the transporter ABCB7 and is characterized by mitochondrial iron deposition and excess of protoporphyrin in erythroid cells. We describe ABCB7 silencing in HeLa cells by performing sequential transfections with siRNAs. The phenotype of the ABCB7-deficient cells was characterized by a strong reduction in proliferation rate that was not rescued by iron supplementation, by evident signs of iron deficiency, and by a large approximately 6-fold increase of iron accumulation in the mitochondria that was poorly available to mitochondrial ferritin. The cells showed an increase of protoporphyrin IX, a higher sensitivity to H 2 O 2 toxicity, and a reduced activity of mitochondrial superoxide dismutase 2 (SOD2), while the activity of mitochondrial enzymes, such as citrate synthase or succinate dehydrogenase, and ATP content were not decreased. In contrast, aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced. The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol, and in the maturation of cytosolic Fe/S enzymes. In addition, the results indicate that anemia in XLSA/A is caused by the accumulation of iron in a form that is not readily usable for heme synthesis. IntroductionIron is essential in all eukaryotes for various vital functions including respiration, gene regulation, and DNA replication and repair. However, iron is also potentially toxic and dysregulation of its homeostasis may contribute to various hematologic, metabolic, and neurodegenerative diseases. 1 Mitochondria play a central role in iron metabolism, since the mitochondrion is the place of synthesis of heme and iron sulfur (Fe/S) proteins, 2 and dysregulation of mitochondrial iron is associated with certain diseases. 3 Among them is Friedreich ataxia, which is caused by deficiency of frataxin, a protein involved in mitochondrial iron trafficking 4 ; the X-linked sideroblastic anemia (XLSA) associated with deficiency of the erythroid-specific ALAS2 5 ; and XLSA/A, X-linked sideroblastic anemia with ataxia associated with defects of the ABC transporter ABCB7. 6 Most of our understanding of mitochondrial iron trafficking comes from the extensive studies done on S cerevisiae that showed that the organelle is the only site for the synthesis of Fe/S clusters, and that this activity is essential for the cell. 2,7 This biochemical pathway necessitates more than 10 different components, which include the cysteine desulphurase Nfs1p; the scaffold proteins Isu1p/Isu2p; chaperones; and the redox enzymes Arh1p, Yah1p, and glutaredoxin-5. 2 The functionality of Fe/S biosynthesis is essential also for the assembly of extramitochondrial Fe/S enzymes, including Leu1p and Rli1p, the latter involved in ribosome biogenesis 8,9 ; but biosynthesis requires a set of accessory proteins that include the ABC transporter named Atm1p, the sulphydryl oxidase Erv1p of mitochondrial intermembrane space, glutathione, the cytosolic P-lo...

Ferritin turnover plays a major role in tissue iron homeostasis, and ferritin malfunction is associated with impaired iron homeostasis and neurodegenerative diseases. In most eukaryotes, ferritin is considered an intracellular protein that stores iron in a nontoxic and bioavailable form. In insects, ferritin is a classically secreted protein and plays a major role in systemic iron distribution. Mammalian ferritin lacks the signal peptide for classical endoplasmic reticulum-Golgi secretion but is found in serum and is secreted via a nonclassical lysosomal secretion pathway. This study applied bioinformatics and biochemical tools, alongside a protein trafficking mouse models, to characterize the mechanisms of ferritin secretion. Ferritin trafficking via the classical secretion pathway was ruled out, and a 2:1 distribution of intracellular ferritin between membrane-bound compartments and the cytosol was observed, suggesting a role for ferritin in the vesicular compartments of the cell. Focusing on nonclassical secretion, we analyzed mouse models of impaired endolysosomal trafficking and found that ferritin secretion was decreased by a BLOC-1 mutation but increased by BLOC-2, BLOC-3, and Rab27A mutations of the cellular trafficking machinery, suggesting multiple export routes. A 13-amino-acid motif unique to ferritins that lack the secretion signal peptide was identified on the BC-loop of both subunits and plays a role in the regulation of ferritin secretion. Finally, we provide evidence that secretion of iron-rich ferritin was mediated via the multivesicular body-exosome pathway. These results enhance our understanding of the mechanism of ferritin secretion, which is an important piece in the puzzle of tissue iron homeostasis.