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Paolo Arosio - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Ferritin.
The international journal of biochemistry & cell biology, 2020Co-Authors: Sonia Levi, Paolo ArosioAbstract:A novel Ferritin type specifically targeted to mitochondria has been recently found in human and mouse. It is structurally and functionally similar to the cytosolic Ferritins, well-characterized molecules found in most living systems which are designed to store and detoxify cellular iron. Cytosolic Ferritins in mammals are ubiquitous while mitochondrial Ferritin expression is restricted mainly to the testis, neuronal cells and islets of Langherans. In addition, it is abundant in the iron-loaded mitochondria of erythroblasts of patients with sideroblastic anaemia. The characterization of recombinant and transfected mitochondrial Ferritin indicated that this protein has a role in protecting mitochondria from iron-induced damage. These data suggest that it is an interesting tool to study the iron metabolism in this organelle. In addition, it may be useful for the diagnosis of myelodysplastic syndromes and in protecting mitochondria from the toxic effects of excess iron.
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cytosolic and mitochondrial Ferritins in the regulation of cellular iron homeostasis and oxidative damage
Biochimica et Biophysica Acta, 2010Co-Authors: Paolo Arosio, Sonia LeviAbstract:Abstract 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.
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Ferritin functions as a proinflammatory cytokine via iron independent protein kinase c zeta nuclear factor kappab regulated signaling in rat hepatic stellate cells
Hepatology, 2009Co-Authors: Richard G Ruddell, Paolo Arosio, D Hoangle, Joanne M Barwood, Paul S Rutherford, Terrance J Piva, Dianne Josephine Watters, Paolo Santambrogio, Grant A RammAbstract:Circulating Ferritin levels reflect body iron stores and are elevated with inflammation in chronic liver injury. H-Ferritin exhibits a number of extrahepatic immunomodulatory properties, although its role in hepatic inflammation and fibrogenesis is unknown. Hepatic stellate cells respond to liver injury through production of proinflammatory mediators that drive fibrogenesis. A specific receptor for Ferritin has been demonstrated on activated hepatic stellate cells, although its identity and its role in stellate cell activation is unclear. We propose that Ferritin acts as a cytokine regulating proinflammatory function via nuclear factor kappaB (NF-B)-regulated signaling in hepatic stellate cell biology. Hepatic stellate cells were treated with tissue Ferritin and iron-free apoFerritin, recombinant H-Ferritins and L-Ferritins, to assess the role of Ferritin versus Ferritin-bound iron in the production of proinflammatory mediators of fibrogenesis, and to determine whether signaling pathways act via a proposed H-Ferritin endocytosis receptor, T cell immunoglobulin-domain and mucin-domain 2 (Tim-2). This study demonstrated that Ferritin activates an iron-independent signaling cascade, involving Tim-2 independent phosphoinositide 3 (PI3)-kinase phosphorylation, protein kinase C zeta (PKC) and p44/p42-mitogen-activated protein kinase, resulting in p50/p65-NF-B activation and markedly enhanced expression of hepatic proinflammatory mediators interleukin-1 (IL-1), inducible nitric oxide synthase (iNOS), regulated on activation normal T cell expressed and secreted (RANTES), inhibitor of kappa B (IB), and intercellular adhesion molecule 1 (ICAM1). Conclusions:This study has defined the role of Ferritin as a proinflammatory mediator of hepatic stellate cell biology acting through the NF-B signaling pathway, and suggests a potential role in the inflammatory processes associated with hepatic fibrogenesis. (HEPATOLOGY 2009;49:887-900.)
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elisa reveals a difference in the structure of substantia nigra Ferritin in parkinson s disease and incidental lewy body compared to control
Parkinsonism & Related Disorders, 2007Co-Authors: Dariusz Koziorowski, Paolo Arosio, Paolo Santambrogio, Andrzej Friedman, Dorota DziewulskaAbstract:Abstract Iron released from Ferritin may trigger oxidative stress leading to progressive neurodegeneration of substantia nigra resulting in Parkinson's disease (PD). Change in the structure of Ferritin may allow an easier efflux of iron. We compared with the use of ELISA the structure of Ferritin (concentrations of H and L Ferritins) in substantia nigra (SN) in ten cases of PD, six of incidental Lewy body (ILB) cases and 20 controls. SN concentration of L Ferritin in ILB (50.6±11.5 ng/mg) and in PD (52.5±26.0) was lower than in control (97.9±54.9). H Ferritin in PD (534.2±223.1) was higher than in ILB (336.9±87.7) and control (374.8±169.3). The decrease of L Ferritin in SN in PD and ILB may suggest that the whole process of neurodegeneration starts with a higher availability of free iron, which is released from the Ferritin shell.
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Ferritin iron homeostasis and oxidative damage
Free Radical Biology and Medicine, 2002Co-Authors: Paolo Arosio, Sonia LeviAbstract:Ferritin is one of the major proteins of iron metabolism. It is almost ubiquitous and tightly regulated by the metal. Biochemical and structural properties of the Ferritins are largely conserved from bacteria to man, although the role in the regulation of iron trafficking varies in the different organisms. Recent studies have clarified some of the major aspects of the reaction between iron and Ferritin, which results in the formation of the iron core and production of hydrogen peroxide. The characterization of cellular models in which Ferritin expression is modulated has shown that the ferroxidase catalytic site on the H-chain has a central role in regulating iron availability. In turn, this has secondary effects on a number of cellular activities, which include proliferation and resistance to oxidative damage. Moreover, the response to apoptotic stimuli is affected by H-Ferritin expression. Altered Ferritin L-chain expression has been found in at least two types of genetic disorders, although its role in the determination of the pathology has not been fully clarified. The recent discovery of a new Ferritin specific for the mitochondria, which is functionally similar to the H-Ferritin, opens new perspectives in the study of the relationships between iron, oxidative damage and free radicals.
Sonia Levi - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Ferritin.
The international journal of biochemistry & cell biology, 2020Co-Authors: Sonia Levi, Paolo ArosioAbstract:A novel Ferritin type specifically targeted to mitochondria has been recently found in human and mouse. It is structurally and functionally similar to the cytosolic Ferritins, well-characterized molecules found in most living systems which are designed to store and detoxify cellular iron. Cytosolic Ferritins in mammals are ubiquitous while mitochondrial Ferritin expression is restricted mainly to the testis, neuronal cells and islets of Langherans. In addition, it is abundant in the iron-loaded mitochondria of erythroblasts of patients with sideroblastic anaemia. The characterization of recombinant and transfected mitochondrial Ferritin indicated that this protein has a role in protecting mitochondria from iron-induced damage. These data suggest that it is an interesting tool to study the iron metabolism in this organelle. In addition, it may be useful for the diagnosis of myelodysplastic syndromes and in protecting mitochondria from the toxic effects of excess iron.
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cytosolic and mitochondrial Ferritins in the regulation of cellular iron homeostasis and oxidative damage
Biochimica et Biophysica Acta, 2010Co-Authors: Paolo Arosio, Sonia LeviAbstract:Abstract 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.
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Ferritin iron homeostasis and oxidative damage
Free Radical Biology and Medicine, 2002Co-Authors: Paolo Arosio, Sonia LeviAbstract:Ferritin is one of the major proteins of iron metabolism. It is almost ubiquitous and tightly regulated by the metal. Biochemical and structural properties of the Ferritins are largely conserved from bacteria to man, although the role in the regulation of iron trafficking varies in the different organisms. Recent studies have clarified some of the major aspects of the reaction between iron and Ferritin, which results in the formation of the iron core and production of hydrogen peroxide. The characterization of cellular models in which Ferritin expression is modulated has shown that the ferroxidase catalytic site on the H-chain has a central role in regulating iron availability. In turn, this has secondary effects on a number of cellular activities, which include proliferation and resistance to oxidative damage. Moreover, the response to apoptotic stimuli is affected by H-Ferritin expression. Altered Ferritin L-chain expression has been found in at least two types of genetic disorders, although its role in the determination of the pathology has not been fully clarified. The recent discovery of a new Ferritin specific for the mitochondria, which is functionally similar to the H-Ferritin, opens new perspectives in the study of the relationships between iron, oxidative damage and free radicals.
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overexpression of wild type and mutated human Ferritin h chain in hela cells in vivo role of Ferritin ferroxidase activity
Journal of Biological Chemistry, 2000Co-Authors: Anna Cozzi, Sonia Levi, Paolo Santambrogio, Barbara Corsi, A Albertini, Paolo ArosioAbstract:Abstract Transfectant HeLa cells were generated that expressed human Ferritin H-chain wild type and an H-chain mutant with inactivated ferroxidase activity under the control of the tetracycline-responsive promoter (Tet-off). The clones accumulated exogenous Ferritins up to levels 14–16-fold over background, half of which were as H-chain homopolymers. This had no evident effect in the mutant Ferritin clone, whereas it induced an iron-deficient phenotype in the H-Ferritin wild type clone, manifested by ∼5-fold increase of IRPs activity, ∼2.5-fold increase of transferrin receptor, ∼1.8-fold increase in iron-transferrin iron uptake, and ∼50% reduction of labile iron pool. Overexpression of the H-Ferritin, but not of the mutant Ferritin, strongly reduced cell growth and increased resistance to H2O2 toxicity, effects that were reverted by prolonged incubation in iron-supplemented medium. The results show that in HeLa cells H-Ferritin regulates the metabolic iron pool with a mechanism dependent on the functionality of the ferroxidase centers, and this affects, in opposite directions, cellular growth and resistance to oxidative damage. This, and the finding that alsoin vivo H-chain homopolymers are much less efficient than the H/L heteropolymers in taking up iron, indicate that functional activity of H-Ferritin in HeLa cells is that predicted from thein vitro data.
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Mechanisms of Ferritin Iron Incorporation: A Study with Recombinant and Mutant Human Ferritins
Iron Biominerals, 1991Co-Authors: Sonia Levi, Alessandra Luzzago, Gianni Cesareni, Paolo Santambrogio, Anna Cozzi, Paolo ArosioAbstract:In mammalian cells iron is stored in a mineral form inside the Ferritin or in its degradation products, the hemosiderins (1,2). Ferritin major function is to address the potentially toxic cellular free-iron inside its cavity, where it forms a polynuclear oxohydroxy ferric core structurally analogous to the ferrihydrite mineral (3,4). Ferritin iron is soluble, non toxic and bioavailable. In order to understand the actual physiological role of Ferritin it is necessary to clarify its mechanism of interaction with iron, and how it directs the formation of the mineral core. Ferritin structure has been defined by prof. Harrison work (3,4). It consists of 24 subunits which assemble to form a cavity 8 nm across, where iron accumulates in a core of variable size, from none up to 4500 atoms per molecule. The structure suggests that Ferritin may act as a sink for iron, but does not provide indications on how it interacts dynamically with the metal (5). In vitro studies have shown that Ferritin readily interacts with ferrous iron in presence of oxygen or other oxidants to form the iron core (6).
Caroline C Philpott - One of the best experts on this subject based on the ideXlab platform.
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each member of the poly r c binding protein 1 pcbp family exhibits iron chaperone activity toward Ferritin
Journal of Biological Chemistry, 2013Co-Authors: Sebastien Leidgens, Timothy L Stemmler, Kimberley Z Bullough, Fengmin Li, Minoo Shakouryelizeh, Toshiki Yabe, Poorna Subramanian, Navin Natarajan, Anjali Nandal, Caroline C PhilpottAbstract:The mechanisms through which iron-dependent enzymes receive their metal cofactors are largely unknown. Poly r(C)-binding protein 1 (PCBP1) is an iron chaperone for Ferritin; both PCBP1 and its paralog PCBP2 are required for iron delivery to the prolyl hydroxylase that regulates HIF1. Here we show that PCBP2 is also an iron chaperone for Ferritin. Co-expression of PCBP2 and human Ferritins in yeast activated the iron deficiency response and increased iron deposition into Ferritin. Depletion of PCBP2 in Huh7 cells diminished iron incorporation into Ferritin. Both PCBP1 and PCBP2 were co-immunoprecipitated with Ferritin in HEK293 cells, and expression of both PCBPs was required for Ferritin complex formation in cells. PCBP1 and -2 exhibited high affinity binding to Ferritin in vitro. Mammalian genomes encode 4 PCBPs, including the minimally expressed PCBPs 3 and 4. Expression of PCBP3 and -4 in yeast activated the iron deficiency response, but only PCBP3 exhibited strong interactions with Ferritin. Expression of PCBP1 and Ferritin in an iron-sensitive, ccc1 yeast strain intensified the toxic effects of iron, whereas expression of PCBP4 protected the cells from iron toxicity. Thus, PCBP1 and -2 form a complex for iron delivery to Ferritin, and all PCBPs may share iron chaperone activity.
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a cytosolic iron chaperone that delivers iron to Ferritin
Science, 2008Co-Authors: Krisztina Z Bencze, Timothy L Stemmler, Caroline C PhilpottAbstract:Ferritins are the main iron storage proteins found in animals, plants, and bacteria. The capacity to store iron in Ferritin is essential for life in mammals, but the mechanism by which cytosolic iron is delivered to Ferritin is unknown. Human Ferritins expressed in yeast contain little iron. Human poly (rC)-binding protein 1 (PCBP1) increased the amount of iron loaded into Ferritin when expressed in yeast. PCBP1 bound to Ferritin in vivo and bound iron and facilitated iron loading into Ferritin in vitro. Depletion of PCBP1 in human cells inhibited Ferritin iron loading and increased cytosolic iron pools. Thus, PCBP1 can function as a cytosolic iron chaperone in the delivery of iron to Ferritin.
Elizabeth C. Theil - One of the best experts on this subject based on the ideXlab platform.
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Ferritins for chemistry and for life
Coordination Chemistry Reviews, 2012Co-Authors: Elizabeth C. Theil, Rabindra K. Behera, Takehiko ToshaAbstract:Abstract Ferritins, highly symmetrical protein nanocages, are reactors for Fe 2+ and dioxygen or hydrogen peroxide that are found in all kingdoms of life and in many different cells of multicellular organisms. They synthesize iron concentrates required for cells to make cofactors of iron proteins (heme, FeS, mono and diiron). The caged Ferritin biominerals, Fe 2 O 3 ·H 2 O are also antioxidants, acting as sinks for iron and oxidants scavenged from damaged proteins; genetic regulation of Ferritin biosynthesis is sensitive to both iron and oxidants. Here, the emphasis is Ferritin oxidoreductase chemistry, Ferritin ion channels for Fe 2+ transit into and out of the protein cage and Fe 3+ O mineral nucleation, and uses of Ferritin cages in nanocatalysis and nanomaterial synthesis. The Ferritin nanocage as reactors for Fe 2+ and oxygen, likely critical in the transition from anaerobic to aerobic life on earth, play central, contemporary roles that balance iron and oxygen chemistry in biology and have emerging roles in nanotechnology.
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absorption of iron from Ferritin is independent of heme iron and ferrous salts in women and rat intestinal segments
Journal of Nutrition, 2012Co-Authors: Elizabeth C. Theil, Huijun Chen, Constanza Miranda, Heinz Janser, Bernd Elsenhans, Marco T Nunez, Fernando Pizarro, Klaus SchumannAbstract:Ferritin iron from food is readily bioavailable to humans and has the potential for treating iron deficiency. Whether Ferritin iron absorption is mechanistically different from iron absorption from small iron complexes/salts remains controversial. Here, we studied iron absorption (RBC 59 Fe) from radiolabeled Ferritin iron (0.5 mg) in healthy women with or without nonFerritin iron competitors, ferrous sulfate, or hemoglobin. A 9-fold excess of non-Ferritin iron competitor had no significant effect on Ferritin iron absorption. Larger amounts of iron (50 mg and a 99-fold excess of either competitor) inhibited iron absorption. To measure transport rates of iron that was absorbed inside Ferritin, rat intestinal segments ex vivo were perfused with radiolabeled Ferritin and compared to perfusion with ferric nitrilotriacetic (Fe-NTA), a well-studied form of chelated iron. Intestinal transport of iron absorbed inside exogenous Ferritin was 14.8% of the rate measured for iron absorbed from chelated iron. In the steady state, endogenous enterocyte Ferritin contained .90% of the iron absorbed from Fe-NTA or Ferritin. We found that Ferritin is a slow release sourceof iron, readily available to humans or animals, based on RBC iron incorporation. Ferritin iron is absorbed by a different mechanism than iron salts/chelates or heme iron. Recognition of a second, nonheme iron absorption process, Ferritin endocytosis, emphasizes the need for more mechanistic studies on Ferritin iron absorption and highlights the potential of Ferritin present in foods such as legumes to contribute to solutions for global iron deficiency. J. Nutr. doi: 10.3945/jn.111.145854.
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concentrating storing and detoxifying iron the Ferritins and hemosiderin
2012Co-Authors: Elizabeth C. TheilAbstract:Ferritins are important in both iron and oxygen metabolism, based on patterns of gene regulation and protein function. The DNA is regulated by oxidants and is coordinated with other antioxidant response genes [1]. The mRNA function regulated by iron and oxygen [2–4] with direct sensing of ferrous ion in the repressor (IRP) complex [5], is coordinated with iron trafficking and oxygen metabolism mRNAs [6]. Ferritin protein converts both cytoplasmic iron (Fe2+) and oxygen (O2), into catalytic product, and mineral precursors in ∼2:1 ratio [7]. A mineral with 2,000 Fe has consumed almost 1,500 dioxygen molecules in mineral formation, decreasing, at least locally, both iron and oxygen in the cytoplasm.
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moving iron in Ferritin leucine 154 a residue near fe iii during mineral buildup minimizes mineral dissolution
IJC-A Vol.50A(03-04) [March-April 2011], 2011Co-Authors: Suranjana Haldar, Elizabeth C. Theil, Takehiko Tosha, Martin Luther KingAbstract:Ferritins, ancient protein nanocages, reversibly synthesize hydrated ferric oxide concentrates; minerals with thousands of iron atoms grow in 8 nm cavities of the 12 nm cages of plant and animal Ferritins. Cells use Ferritin iron for iron-protein cofactor synthesis and as a trap for reactive iron from damaged iron-proteins. Recent Ferritin structural studies show the iron entry path through iron ion channels, oxidoreductase sites and nucleation channels, a distance of ~ 5 nm from one end of the cage subunits (4 α-helix bundles) to the other. We now show that conserved L154, at the cavity entrance in a loop between helix 4 and a fifth short helix, slows mineral dissolution (50% mineral dissolution was >7 times faster in L154G Ferritin). The effects on iron exit of leucine/glycine replacement in residue 154 at the end of iron entry path shows convergence of the iron entry and exit at L154 on the cage edge. The L154-dependent cage stabilization mechanism and the path that Fe(II) follows from the mineral surface to the Ferritin protein are problems that remain unsolved in understanding the complex, eukaryotic Ferritin protein cages that evolved for natural iron metabolism and are also used for imaging, nanocatalysis and nanomaterials.
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Ferritins: iron/oxygen biominerals in protein nanocages
JBIC Journal of Biological Inorganic Chemistry, 2006Co-Authors: Elizabeth C. Theil, Manolis MatzapetakisAbstract:Ferritin protein nanocages that form iron oxy biominerals in the central nanometer cavity are nature’s answer to managing iron and oxygen; gene deletions are lethal in mammals and render bacteria more vulnerable to host release of antipathogen oxidants. The multifunctional, multisubunit proteins couple iron with oxygen (maxi-Ferritins) or hydrogen peroxide (mini-Ferritins) at catalytic sites that are related to di-iron sites oxidases, ribonucleotide reductase, methane monooxygenase and fatty acid desaturases, and synthesize mineral precursors. Gated pores, distributed symmetrically around the Ferritin cages, control removal of iron by reductants and chelators. Gene regulation of Ferritin, long known to depend on iron and, in animals, on a noncoding messenger RNA (mRNA) structure linked in a combinatorial array to functionally related mRNA of iron transport, has recently been shown to be linked to an array of proteins for antioxidant responses such as thioredoxin and quinone reductases. Ferritin DNA responds more to oxygen signals, and Ferritin mRNA responds more to iron signals. Ferritin genes (DNA and RNA) and protein function at the intersection of iron and oxygen chemistry in biology.
Mahmood Jeddi-tehrani - One of the best experts on this subject based on the ideXlab platform.
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Production and characterization of a murine monoclonal antibody against human Ferritin
Avicenna Journal of Medical Biotechnology, 2013Co-Authors: Ali Ahmad Bayat, Ahmad R. Mahmoudi, Jafar Mahmoudian, Omid Yeganeh, Reza Bahjati Ardekani, Farzaneh Haghighat-noutash, Roya Ghods, Amir Hassan Zarnani, Mahmood Jeddi-tehraniAbstract:BACKGROUND: Ferritin is an iron storage protein, which plays a key role in iron metabolism. Measurement of Ferritin level in serum is one of the most useful indicators of iron status and also a sensitive measurement of iron deficiency. Monoclonal antibodies may be useful as a tool in various aspects of Ferritin investigations. In this paper, the production of a murine monoclonal antibody (mAb) against human Ferritin was reported.\n\nMETHODS: Balb/c mice were immunized with purified human Ferritin and splenocytes of hyper immunized mice were fused with Sp2/0 myeloma cells. After four times of cloning by limiting dilution, a positive hybridoma (clone: 2F9-C9) was selected by ELISA using human Ferritin. Anti-Ferritin mAb was purified from culture supernatants by affinity chromatography.\n\nRESULTS: Determination of the antibody affinity for Ferritin by ELISA revealed a relatively high affinity (2.34×10(9) M (-1)) and the isotype was determined to be IgG2a. The anti-Ferritin mAb 2F9-C9 reacted with 79.4% of Hela cells in flow cytometry. The antibody detected a band of 20 kDa in K562 cells, murine and human liver lysates, purified Ferritin in Western blot and also Ferritin in human serum.\n\nCONCLUSION: This mAb can specifically recognize Ferritin and may serve as a component of Ferritin diagnostic kit if other requirements of the kit are met.