Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewFerritins: A family of molecules for iron storage, antioxidation and more
Introduction
Ferritin was first described by Laufberger in 1937 who purified it by crystallization with cadmium salts [1]. It has been characterized ever since, and thus is probably the most studied iron protein, after haemoglobin. It is remarkably resistant to denaturants, including heating to > 80 °C, it often contains peculiar large electron-dense iron cores and it elicits high affinity antibodies, all properties that facilitate its recognition and allowed to verify that ferritin is essentially ubiquitous and expressed in most eubacteria, archea, plants and animals, with the notable exception of yeasts. Thus, ferritin is probably the most common and ancient molecule of iron homeostasis and carries some fundamental functions. Most of the ferritin roles in all the organisms have been attributed to its capacity to bind and sequester intracellular iron with mechanisms that have been described in various reviews [2], [3]. However, ferritin seems to have also roles other than simply storing iron, some of which are described in this work.
Section snippets
Ferritin structure
The ferritin properties as iron storage molecules have been described in previous reviews [2], [4], [5]. The typical ferritins are composed of 24 subunits, which fold in a 4-helical bundle, and in coming together they form an almost spherical protein shell with 4,3,2 point symmetry (Fig. 1). The major property of the shell is a large cavity, designed to accommodate up to 4000 Fe atoms, which communicates with the solvent via six hydrophilic channels on the 3-fold symmetry axes. Other channels
Ferritin iron oxidation and radical detoxification
The main in vitro reaction of any ferritin type is to react with Fe(II) and induce its oxidation and deposition inside the cavity in a ferric oxohydroxide core which is structurally similar to the mineral ferrihydrite [2]. This reaction is considered analogous to the one occurring in the cells, and it is biologically important for two reasons: first, the very high iron binding capacity (up to 4000 Fe atoms per molecule) concentrates iron in a compact and safe form which can be made readily
Ferritin iron release
Ferritin retains a large amount of iron in most organisms, in mammals it is second only to hemoglobin. Although it is well known that ferritin iron is recycled and readily available for cellular needs, less is known on the physiological mechanisms of its release. In vitro studies showed that the iron of the ferritin core is stable in the absence of reducing agents, does not exchange among molecules and can be released only slowly by strong Fe(III) chelators such as desferroxamine [3]. However,
Regulation of ferritin expression
Just as the ferritin structure is highly conserved in bacteria, plants and animals, so are the basic stimuli that regulate its expression: iron availability and response to oxidative stress (reviewed in ref. [35]). This is consistent with the major and common function of all ferritins, which is to sequester iron and consume dioxygen or peroxides, and therefore limit free radical production. In bacteria and plants the regulation occurs only at a transcriptional level, and the two types of
Cellular and animal models
The study of E. coli deletion mutant strains showed that ferritin and bacterioferritin provide intracellular iron reserves for use when external supplies are restricted, and Dps are employed to protect the chromosome from iron-induced free radical damage [56] and allow bacterial pathogens that lack catalase to survive in an aerobic environment and resist to peroxide stress [57]. In C. elegans the mutants lacking one of the two ferritin proteins, FTN-1 showed significantly reduced life-span upon
Non-iron mediated roles of intracellular ferritins
Indications that ferritin may have functions apparently unrelated to its capacity to bind iron go back to the early days. For example in 1950 Shorr et al. [77] suggested that hepatic ferritin has an antidiuretic effect, but this has not been confirmed. A list of the proposed functions of the various types of mammalian ferritin is presented in Table 2. Sherrer et al. [78] demonstrated that the prosome-like particle found in duck erythroblasts is the same as ferritin. This particle is tightly
Nuclear ferritins
Intranuclear ferritin has been initially observed in iron overload in mice, rats and baboons [93], [94], [95]. It was found in various cell types, which include hepatocytes, bone-marrow macrophages, muscle and nerve cells, some brain tumor cells and glial cell lines, neuronal cultures of the rat and pig brains [96], [97], chicken mature erythrocytes [89] and chicken corneal endothelial cells [98]. The embryonic chicken corneal epithelial cells have been studied in detail, showing that the
Mitochondrial ferritin
The analysis of human and mouse cDNA libraries revealed the presence of a novel ferritin precursor with high identity to the cytosolic H ferritin, characterized by a long N-terminal extension of 56–60 amino acids containing a mitochondrial localization sequence [107]. The product of this intronless gene was specifically taken up by mitochondria and processed to form a stable ferritin shell with ferroxidase activity and functional in incorporating iron [108], [109]. The amino acid sequence of
Secretory ferritins
In insects and worms the ferritin chains are expressed as precursors with a leader sequence for export, and in fact they are found secreted in the yolk fluid or inside secretory granules [59], [128]. Mammalian ferritins lack leader sequences but they are found in body fluids, such as serum, CSF and synovial fluids. The one in serum counts for a minor proportion of total body ferritin, but it is clinically important, since its level is a useful index of body iron status, and therefore largely
Ferritin immunotherapy
Abnormal ferritin expression has been observed in a large number of tumor types, and it has been suggested that it may act as a tumor marker in neuroblastoma and other cancers [149]. Based in the earlier observation that ferritin may be tumor antigens, approaches have been attempted to verify if anti ferritin antibodies may specifically target tumor cells in vivo. Tumors transplanted in animal models were targeted by radiolabelled anti-ferritin antibodies, and in various clinical trials
Genetic ferritin disorders
FtMt is a short intronless gene, but no reports appeared on its genetic variation in sideroblastic anemia or other disorders. A single causative mutation of H ferritin has been reported so far. It was found in a Japanese patient affected by dominant inherited iron overload, and the mutation modified the regulatory IRE sequence, paradoxically causing H ferritin downregulation [155]. A more exhaustive study of 660 subjects with abnormalities in serum ferritin and iron status identified only two
Conclusions and future directions
Ferritin has been studied for more than 70 years, but still remains an interesting molecule that keeps showing new and unexpected characteristics. We now know that it is an active molecule that regulates cellular iron availability and key reagents for oxidative damage, a finding that explains in part its presence in almost all cell types and cellular compartments. During its long history the protein evolved and adapted to fulfill specific requirements, for example it acquired the capacity to
Acknowledgments
We are grateful to Prof. Clara Camaschella and Prof. Sonia Levi for reading the manuscript. The work was partially supported by Murst-Cofin-2006 to PA, by Telethon-Italy grant GGP05141 to PA, and by Euroiron1 grant.
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