Renal control of disease tolerance to malaria.

Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.

Ferritinophagy is not required for colon cancer cell growth.

Ferritinophagy is a form of selective autophagy responsible for degrading intracellular ferritin, mediated by nuclear receptor coactivator 4 (NCOA4). NCOA4 plays significant roles in systemic iron homeostasis, and its disruption leads to simultaneous anemia and susceptibility to iron overload. The importance of iron colorectal cancer pathogenesis is well studied; however, the role of ferritinophagy in colon cancer cell growth has not been assessed. Disruption of ferritinophagy via NCOA4 knockout leads to only marginal differences in growth under basal and iron-restricted conditions. Moreover, NCOA4 played no significant role in cell death induced by 5-fluorouracil and erastin. Western blotting analysis for ferritin and transferrin receptor 1 found a dose-dependent effect on expression in both proteins in wild-type and NCOA4 knockout cell lines, but further investigation revealed no difference in growth response when treated at both high and low doses. Our data demonstrate a marginal role for ferritinophagy in growth both under normal and cytotoxic conditions in colon cancer cells, as well as a possible compensatory mechanism in colon cancer cells in response to ferroptosis induction.

Identification of human ferritin, heavy polypeptide 1 (FTH1) and yeast RGI1 (YER067W) as pro-survival sequences that counteract the effects of Bax and copper in Saccharomyces cerevisiae.

Ferritin is a sub-family of iron binding proteins that form multi-subunit nanotype iron storage structures and prevent oxidative stress induced apoptosis. Here we describe the identification and characterization of human ferritin, heavy polypeptide 1 (FTH1) as a suppressor of the pro-apoptotic murine Bax sequence in yeast. In addition we demonstrate that FTH1 is a general pro-survival sequence since it also prevents the cell death inducing effects of copper when heterologously expressed in yeast. Although ferritins are phylogenetically widely distributed and are present in most species of Bacteria, Archaea and Eukarya, ferritin is conspicuously absent in most fungal species including Saccharomyces cerevisiae. An in silico analysis of the yeast proteome lead to the identification of the 161 residue RGI1 (YER067W) encoded protein as a candidate for being a yeast ferritin. In addition to sharing 20% sequence identity with the 183 residue FTH1, RGI1 also has similar pro-survival properties as ferritin when overexpressed in yeast. Analysis of recombinant protein by SDS-PAGE and by electron microscopy revealed the expected formation of higher-order structures for FTH1 that was not observed with Rgi1p. Further analysis revealed that cells overexpressing RGI1 do not show increased resistance to iron toxicity and do not have enhanced capacity to store iron. In contrast, cells lacking RGI1 were found to be hypersensitive to the toxic effects of iron. Overall, our results suggest that Rgi1p is a novel pro-survival protein whose function is not related to ferritin but nevertheless it may have a role in regulating yeast sensitivity to iron stress.

Ferritins: furnishing proteins with iron.

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe(2+) oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores, consider how iron might be released from ferritins, and examine in detail how three selected ferritins oxidise Fe(2+) to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins.

Nuclear ferritin mediated regulation of JNK signaling in corneal epithelial cells.

Corneal epithelial (CE) cells are exposed to environmental insults (e.g., UV-irradiation), yet they suffer little damage. Our previous studies suggest that chicken CE cells have a novel form of protection involving having ferritin in a nuclear location where it can bind to DNA and sequester free iron. Here we describe another potential nuclear ferritin-mediated protective mechanism: the down-regulation of the JNK signaling pathway. The JNK pathway has been shown by others to promote apoptosis in response to cell damage and also to be activated in CE cell lines following exposure to UV radiation. Here we show in COS7 reporter cell lines that the expression of ferritin in a nuclear localization significantly down-regulates the JNK pathway (p = 5.7 × 10(-6)), but has no effect on the NFkB or the Erk pathways. In organ cultures of embryonic chicken corneas, we observed that inhibiting the synthesis of nuclear ferritin in CE cells, using the iron-chelating molecule deferoxamine, led to an increase in JNK signaling, as measured by phospho-JNK levels compared to CE cells with nuclear ferritin. Furthermore, the chemical inhibition of the JNK pathway using the molecule AS601245 decreased the production of nuclear ferritin. Taken together, these observations suggest that in CE cells a feedback-loop exists in which JNK signaling increases the production of nuclear ferritin and, in turn, nuclear ferritin decreases the activity of the JNK signaling pathway.

Ferritin is the key to dietary iron absorption and tissue iron detoxification in Drosophila melanogaster.

Mammalian ferritin is predominantly in the cytosol, with a minor portion found in plasma. In most insects, including Drosophila melanogaster, ferritin belongs to the secretory type. The functional role of secretory ferritin in iron homeostasis remains poorly understood in insects as well as in mammalians. Here we used Drosophila to dissect the involvement of ferritin in insect iron metabolism. Midgut-specific knockdown of ferritin resulted in iron accumulation in the gut but systemic iron deficiency (37% control), accompanied by retarded development and reduced survival (3% survival), and was rescued by dietary iron supplementation (50% survival) or exacerbated by iron depletion (0% survival). These results suggest an essential role of ferritin in removing iron from enterocytes across the basolateral membrane. Expression of wild-type ferritin in the midgut, especially in the iron cell region, could significantly rescue ferritin-null mutants (first-instar larvae rescued up to early adults), indicating iron deficiency as the major cause of early death for ferritin flies. In many nonintestinal tissues, tissue-specific ferritin knockdown also caused local iron accumulation (100% increase) and resulted in severe tissue damage, as evidenced by cell loss. Overall, our study demonstrated Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification.

Uptake of H-ferritin by Glioblastoma stem cells and its impact on their invasion capacity.

PURPOSE: Iron acquisition is key to maintaining cell survival and function. Cancer cells in general are considered to have an insatiable iron need. Iron delivery via the transferrin/transferrin receptor pathway has been the canonical iron uptake mechanism. Recently, however, our laboratory and others have explored the ability of ferritin, particularly the H-subunit, to deliver iron to a variety of cell types. Here, we investigate whether Glioblastoma (GBM) initiating cells (GICs), a small population of stem-like cells, are known for their iron addiction and invasive nature acquire exogenous ferritin, as a source of iron. We further assess the functional impact of ferritin uptake on the invasion capacity of the GICs. METHODS: To establish that H-ferritin can bind to human GBM, tissue-binding assays were performed on samples collected at the time of surgery. To interrogate the functional consequences of H-ferritin uptake, we utilized two patient-derived GIC lines. We further describe H-ferritin's impact on GIC invasion capacity using a 3D invasion assay. RESULTS: H-ferritin bound to human GBM tissue at the amount of binding was influenced by sex. GIC lines showed uptake of H-ferritin protein via transferrin receptor. FTH1 uptake correlated with a significant decrease in the invasion capacity of the cells. H-ferritin uptake was associated with a significant decrease in the invasion-related protein Rap1A. CONCLUSION: These findings indicate that extracellular H-ferritin participates in iron acquisition to GBMs and patient-derived GICs. The functional significance of the increased iron delivery by H-ferritin is a decreased invasion capacity of GICs potentially via reduction of Rap1A protein levels.

[Vitamin B12 and iron deficiencies: from diagnostic to follow-up]. / Carences en vitamine B12 et fer: du diagnostic au suivi.

Vitamin B12 and iron deficiencies are common problems in consultations of general internal medicine. They cause different symptoms that can be non-specific. This article makes it possible, from a clinical frame of reference, to answer the following questions: What value of vitamin B12 should we consider a "deficiency", and what is the role of methylmalonate? What is the role of vitamin B12 oral supplements? How should we interpret values of ferritine? How should iron deficiency be investigated? What is the place of intravenous iron administration?

Phytoferritin and its implications for human health and nutrition.

BACKGROUND: Plant and animal ferritins stem from a common ancestor, but plant ferritins exhibit various features that are different from those of animal ferritins. Phytoferritin is observed in plastids (e.g., chloroplasts in leaves, amyloplasts in tubers and seeds), whereas animal ferritin is largely found in the cytoplasm. The main difference in structure between plant and animal ferritins is the two specific domains (TP and EP) at the N-terminal sequence of phytoferritin, which endow phytoferritin with specific iron chemistry. As a member of the nonheme iron group of dietary iron sources, phytoferritin consists of 24 subunits that assemble into a spherical shell storing up to approximately 2000 Fe(3+) in the form of an iron oxyhydroxide-phosphate mineral. This feature is distinct from small molecule nonheme iron existing in cereals, which has poor bioavailability. SCOPE OF REVIEW: This review focuses on the relationship between structure and function of phytoferritin and the recent progress in the use of phytoferritin as iron supplement. MAJOR CONCLUSIONS: Phytoferritin, especially from legume seeds, represents a novel alternative dietary iron source. GENERAL SIGNIFICANCE: An understanding of the chemistry and biology of phytoferritin, its interaction with iron, and its stability against gastric digestion is beneficial to design diets that will be used for treatment of global iron deficiency.

Ferritin in the field of nanodevices.

Biomineralization of ferritin core has been extended to the artificial synthesis of homogeneous metal complex nanoparticles (NPs) and semiconductor NPs. The inner cavity of apoferritin is an ideal spatially restricted chemical reaction chamber for NP synthesis. The obtained ferritin (biocomplexes, NP and the surrounding protein shell) has attracted great interest among researchers in the field of nanodevices. Ferritins were delivered onto specific substrate locations in a one-by-one manner or a hexagonally close-packed array through ferritin outer surface interactions. After selective elimination of protein shells from the ferritin, bare NPs were left at the positions where they were delivered. The obtained NPs were used as catalysts for carbon nanotube (CNT) growth and metal induced lateral crystallization (MILC), charge storage nodes of floating gate memory, and nanometer-scale etching masks, which could not be performed by other methods.

Serum ferritin: Past, present and future.

BACKGROUND: Serum ferritin was discovered in the 1930s, and was developed as a clinical test in the 1970s. Many diseases are associated with iron overload or iron deficiency. Serum ferritin is widely used in diagnosing and monitoring these diseases. SCOPE OF REVIEW: In this chapter, we discuss the role of serum ferritin in physiological and pathological processes and its use as a clinical tool. MAJOR CONCLUSIONS: Although many aspects of the fundamental biology of serum ferritin remain surprisingly unclear, a growing number of roles have been attributed to extracellular ferritin, including newly described roles in iron delivery, angiogenesis, inflammation, immunity, signaling and cancer. GENERAL SIGNIFICANCE: Serum ferritin remains a clinically useful tool. Further studies on the biology of this protein may provide new biological insights.

Insect ferritins: Typical or atypical?

Insects transmit millions of cases of disease each year, and cost millions of dollars in agricultural losses. The control of insect-borne diseases is vital for numerous developing countries, and the management of agricultural insect pests is a very serious business for developed countries. Control methods should target insect-specific traits in order to avoid non-target effects, especially in mammals. Since insect cells have had a billion years of evolutionary divergence from those of vertebrates, they differ in many ways that might be promising for the insect control field-especially, in iron metabolism because current studies have indicated that significant differences exist between insect and mammalian systems. Insect iron metabolism differs from that of vertebrates in the following respects. Insect ferritins have a heavier mass than mammalian ferritins. Unlike their mammalian counterparts, the insect ferritin subunits are often glycosylated and are synthesized with a signal peptide. The crystal structure of insect ferritin also shows a tetrahedral symmetry consisting of 12 heavy chain and 12 light chain subunits in contrast to that of mammalian ferritin that exhibits an octahedral symmetry made of 24 heavy chain and 24 light chain subunits. Insect ferritins associate primarily with the vacuolar system and serve as iron transporters-quite the opposite of the mammalian ferritins, which are mainly cytoplasmic and serve as iron storage proteins. This review will discuss these differences.

Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage.

BACKGROUND: Ferritin structure is designed to maintain large amounts of iron in a compact and bioavailable form in solution. All ferritins induce fast Fe(II) oxidation in a reaction catalyzed by a ferroxidase center that consumes Fe(II) and peroxides, the reagents that produce toxic free radicals in the Fenton reaction, and thus have anti-oxidant effects. Cytosolic ferritins are composed of the H- and L-chains, whose expression are regulated by iron at a post-transcriptional level and by oxidative stress at a transcriptional level. The regulation of mitochondrial ferritin expression is presently unclear. SCOPE OF REVIEW: The scope of the review is to update recent progress regarding the role of ferritins in the regulation of cellular iron and in the response to oxidative stress with particular attention paid to the new roles described for cytosolic ferritins, to genetic disorders caused by mutations of the ferritin L-chain, and new findings on mitochondrial ferritin. MAJOR CONCLUSIONS: The new data on the adult conditional knockout (KO) mice for the H-chain and on the hereditary ferritinopathies with mutations that reduce ferritin functionality strongly indicate that the major role of ferritins is to protect from the oxidative damage caused by iron deregulation. In addition, the study of mitochondrial ferritin, which is not iron-regulated, indicates that it participates in the protection against oxidative damage, particularly in cells with high oxidative activity. GENERAL SIGNIFICANCE: Ferritins have a central role in the protection against oxidative damage, but they are also involved in non-iron-dependent processes.

The Ferritin-like superfamily: Evolution of the biological iron storeman from a rubrerythrin-like ancestor.

BACKGROUND: The Ferritins are part of the extensive 'Ferritin-like superfamily' which have diverse functions but are linked by the presence of a common four-helical bundle domain. The role performed by Ferritins as the cellular repository of excess iron is unique. In many ways Ferritins act as tiny organelles in their ability to secrete iron away from the delicate machinery of the cell, and then to release it again in a controlled fashion avoiding toxicity. The Ferritins are ancient proteins, being common in all three domains of life. This ubiquity reflects the key contribution that Ferritins provide in achieving iron homeostasis. SCOPE OF THE REVIEW: This review compares the features of the different Ferritins and considers how they, and other members of the Ferritin-like superfamily, have evolved. It also considers relevant features of the eleven other known families within the Ferritin-like superfamily, particularly the highly diverse rubrerythrins. MAJOR CONCLUSIONS: The Ferritins have travelled a considerable evolutionary journey, being derived from far more simplistic rubrerythrin-like molecules which play roles in defence against toxic oxygen species. The forces of evolution have moulded such molecules into three distinct types of iron storing (or detoxifying) protein: the classical and universal 24-meric ferritins; the haem-containing 24-meric bacterioferritins of prokaryotes; and the prokaryotic 12-meric Dps proteins. These three Ferritin types are similar, but also possess unique properties that distinguish them and enable then to achieve their specific physiological purposes. GENERAL SIGNIFICANCE: A wide range of biological functions have evolved from a relatively simple structural unit.

Could a dysfunction of ferritin be a determinant factor in the aetiology of some neurodegenerative diseases?

BACKGROUND: The concentration of iron in the brain increases with aging. Furthermore, it has also been observed that patients suffering from neurological diseases (e.g. Parkinson, Alzheimer...) accumulate iron in the brain regions affected by the disease. Nevertheless, it is still not clear whether this accumulation is the initial cause or a secondary consequence of the disease. Free iron excess may be an oxidative stress source causing cell damage if it is not correctly stored in ferritin cores as a ferric iron oxide redox-inert form. SCOPE: Both, the composition of ferritin cores and their location at subcellular level have been studied using analytical transmission electron microscopy in brain tissues from progressive supranuclear palsy (PSP) and Alzheimer disease (AD) patients. MAJOR CONCLUSIONS: Ferritin has been mainly found in oligodendrocytes and in dystrophic myelinated axons from the neuropili in AD. In relation to the biomineralization of iron inside the ferritin shell, several different crystalline structures have been observed in the study of physiological and pathological ferritin. Two cubic mixed ferric-ferrous iron oxides are the major components of pathological ferritins whereas ferrihydrite, a hexagonal ferric iron oxide, is the major component of physiological ferritin. We hypothesize a dysfunction of ferritin in its ferroxidase activity. GENERAL SIGNIFICANCE: The different mineralization of iron inside ferritin may be related to oxidative stress in olygodendrocites, which could affect myelination processes with the consequent perturbation of information transference.

The ferritin superfamily: Supramolecular templates for materials synthesis.

Members of the ferritin superfamily are multi-subunit cage-like proteins with a hollow interior cavity. These proteins possess three distinct surfaces, i.e. interior and exterior surfaces of the cages and interface between subunits. The interior cavity provides a unique reaction environment in which the interior reaction is separated from the external environment. In biology the cavity is utilized for sequestration of irons and biomineralization as a mechanism to render Fe inert and sequester it from the external environment. Material scientists have been inspired by this system and exploited a range of ferritin superfamily proteins as supramolecular templates to encapsulate nanoparticles and/or as well-defined building blocks for fabrication of higher order assembly. Besides the interior cavity, the exterior surface of the protein cages can be modified without altering the interior characteristics. This allows us to deliver the protein cages to a targeted tissue in vivo or to achieve controlled assembly on a solid substrate to fabricate higher order structures. Furthermore, the interface between subunits is utilized for manipulating chimeric self-assembly of the protein cages and in the generation of symmetry-broken Janus particles. Utilizing these ideas, the ferritin superfamily has been exploited for development of a broad range of materials with applications from biomedicine to electronics.

Nuclear ferritin: A new role for ferritin in cell biology.

BACKGROUND: Ferritin has been traditionally considered a cytoplasmic iron storage protein. However, several studies over the last two decades have reported the nuclear localization of ferritin, specifically H-ferritin, in developing neurons, hepatocytes, corneal epithelial cells, and some cancer cells. These observations encouraged a new perspective on ferritin beyond iron storage, such as a role in the regulation of iron accessibility to nuclear components, DNA protection from iron-induced oxidative damage, and transcriptional regulation. SCOPE OF REVIEW: This review will address the translocation and functional significance of nuclear ferritin in the context of human development and disease. MAJOR CONCLUSIONS: The nuclear translocation of ferritin is a selective energy-dependent process that does not seem to require a consensus nuclear localization signal. It is still unclear what regulates the nuclear import/export of ferritin. Some reports have implicated the phosphorylation and O-glycosylation of the ferritin protein in nuclear transport; others suggested the existence of a specific nuclear chaperone for ferritin. The data argue strongly for nuclear ferritin as a factor in human development and disease. Ferritin can bind and protect DNA from oxidative damage. It also has the potential of playing a regulatory role in transcription. GENERAL SIGNIFICANCE: Nuclear ferritin represents a novel new outlook on ferritin functionality beyond its classical role as an iron storage molecule.

Ferritins and iron storage in plants.

Iron is essential for both plant productivity and nutritional quality. Improving plant iron content was attempted through genetic engineering of plants overexpressing ferritins. However, both the roles of these proteins in the plant physiology, and the mechanisms involved in the regulation of their expression are largely unknown. Although the structure of ferritins is highly conserved between plants and animals, their cellular localization differ. Furthermore, regulation of ferritin gene expression in response to iron excess occurs at the transcriptional level in plants, in contrast to animals which regulate ferritin expression at the translational level. In this review, our knowledge of the specific features of plant ferritins is presented, at the level of their (i) structure/function relationships, (ii) cellular localization, and (iii) synthesis regulation during development and in response to various environmental cues. A special emphasis is given to their function in plant physiology, in particular concerning their respective roles in iron storage and in protection against oxidative stress. Indeed, the use of reverse genetics in Arabidopsis recently enabled to produce various knock-out ferritin mutants, revealing strong links between these proteins and protection against oxidative stress. In contrast, their putative iron storage function to furnish iron during various development processes is unlikely to be essential. Ferritins, by buffering iron, exert a fine tuning of the quantity of metal required for metabolic purposes, and help plants to cope with adverse situations, the deleterious effects of which would be amplified if no system had evolved to take care of free reactive iron.

The two Dps of Edwardsiella tarda are involved in resistance against oxidative stress and host infection.

DNA-binding protein from starved cells (Dps) is a member of ferritin-like proteins that exhibit properties of nonspecific DNA binding and iron oxidation and storage. Although studies of Dps from many bacterial species have been reported, no investigations on Dps from fish pathogens have been documented. In this study, we examined the biological function of two Dps proteins, Dps1 and Dps2, from Edwardsiella tarda, an important fish bacterial pathogen that can also infect humans. Dps1 and Dps2 are, respectively, 163- and 174-residue in length and each contains the conserved ferroxidase center of Dps. Expression of dps1 and dps2 was growth phase-dependent and reached high levels in stationary phase. Purified recombinant Dps1 and Dps2 were able to mediate iron oxidation by H(2)O(2) and bind DNA. Compared to the wild type strain, (i) the dps1 mutant (TXDps1) and the dps2 mutant (TXDps2) were unaffected in growth, while the dps2 mutant with interfered dps1 expression (TXDps2RI) exhibited a prolonged lag phase; (ii) TXDps1, TXDps2, and especially TXDps2RI were significantly reduced in H(2)O(2) and UV tolerance and impaired in the capacity to invade into host tissues and replicate in head kidney macrophages; (iii) TXDps1, TXDps2, and TXDps2RI induced stronger macrophage respiratory burst activity and thus were defective in the ability to block the bactericidal response of macrophages. Taken together, these results indicate that Dps1 and Dps2 are functional analogues that possess ferroxidase activity and DNA binding capacity and are required for optimum oxidative stress resistance and full bacterial virulence.

Tightly controlled response to oxidative stress; an important factor in the tolerance of Bacteroides fragilis.

The exposure of Bacteroides fragilis to highly oxygenated tissues induces an oxidative stress due to a shift from the reduced condition of the gastrointestinal tract to an aerobic environment of host tissues. The potent and effective responses to reactive oxygen species (ROS) make the B. fragilis tolerant to atmospheric oxygen for several days. The response to oxidative stress in B. fragilis is a complicated event that is induced and regulated by different agents. In this review, we will focus on the B. fragilis response to oxidative stress and present an overview of the regulators of responses to oxidative stress in this bacterium.