Editorial

4 pages, 193 KiB

Open AccessEditorial

New Advances in Iron Metabolism, Ferritin and Hepcidin Research

by Paolo Arosio

Int. J. Mol. Sci. 2022, 23(23), 14700; https://doi.org/10.3390/ijms232314700 - 25 Nov 2022

Cited by 1 | Viewed by 1344

The interest in the regulation of iron metabolism has increased in recent years with the clarification of the mechanism by which hepcidin regulates systemic iron homeostasis and the discovery of ferritinophagy, the major mechanism of ferritin degradation, which plays a major role in [...] Read more.

The interest in the regulation of iron metabolism has increased in recent years with the clarification of the mechanism by which hepcidin regulates systemic iron homeostasis and the discovery of ferritinophagy, the major mechanism of ferritin degradation, which plays a major role in intracellular iron homeostasis and ferroptosis [...] Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

Research

Jump to: Editorial, Review

11 pages, 1087 KiB

Open AccessArticle

Iron Mobilization from Ferritin in Yeast Cell Lysate and Physiological Implications

by Gideon L. Smith, Ayush K. Srivastava, Aliaksandra A. Reutovich, Nathan J. Hunter, Paolo Arosio, Artem Melman and Fadi Bou-Abdallah

Int. J. Mol. Sci. 2022, 23(11), 6100; https://doi.org/10.3390/ijms23116100 - 29 May 2022

Cited by 7 | Viewed by 2680

Abstract

Most in vitro iron mobilization studies from ferritin have been performed in aqueous buffered solutions using a variety of reducing substances. The kinetics of iron mobilization from ferritin in a medium that resembles the complex milieu of cells could dramatically differ from those [...] Read more.

Most in vitro iron mobilization studies from ferritin have been performed in aqueous buffered solutions using a variety of reducing substances. The kinetics of iron mobilization from ferritin in a medium that resembles the complex milieu of cells could dramatically differ from those in aqueous solutions, and to our knowledge, no such studies have been performed. Here, we have studied the kinetics of iron release from ferritin in fresh yeast cell lysates and examined the effect of cellular metabolites on this process. Our results show that iron release from ferritin in buffer is extremely slow compared to cell lysate under identical experimental conditions, suggesting that certain cellular metabolites present in yeast cell lysate facilitate the reductive release of ferric iron from the ferritin core. Using filtration membranes with different molecular weight cut-offs (3, 10, 30, 50, and 100 kDa), we demonstrate that a cellular component >50 kDa is implicated in the reductive release of iron. When the cell lysate was washed three times with buffer, or when NADPH was omitted from the solution, a dramatic decrease in iron mobilization rates was observed. The addition of physiological concentrations of free flavins, such as FMN, FAD, and riboflavin showed about a two-fold increase in the amount of released iron. Notably, all iron release kinetics occurred while the solution oxygen level was still high. Altogether, our results indicate that in addition to ferritin proteolysis, there exists an auxiliary iron reductive mechanism that involves long-range electron transfer reactions facilitated by the ferritin shell. The physiological implications of such iron reductive mechanisms are discussed. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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13 pages, 1909 KiB

Open AccessArticle

New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation

by Lídia Romero-Cortadellas, Gonzalo Hernández, Xènia Ferrer-Cortès, Laura Zalba-Jadraque, José Luis Fuster, Mar Bermúdez-Cortés, Ana María Galera-Miñarro, Santiago Pérez-Montero, Cristian Tornador and Mayka Sánchez

Int. J. Mol. Sci. 2022, 23(8), 4406; https://doi.org/10.3390/ijms23084406 - 15 Apr 2022

Cited by 4 | Viewed by 2717

Abstract

Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations [...] Read more.

Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far. Here, we report two novel cases of this disease. The first proband is homozygous for a new SLC11A2 splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a SLC11A2 splicing mutation in homozygosity. Splicing studies performed in this work confirm its pathogenicity. The second proband harbors the previously reported DMT1 G75R mutation in homozygosis. Functional studies with the G75R mutation in HuTu 80 cells demonstrate that this mutation results in improper DMT1 accumulation in lysosomes, which correlates with a significant decrease in DMT1 levels in patient-derived lymphoblast cell lines (LCLs). We also suggest that recombinant erythropoietin would be an adequate therapeutic approach for AHMIO1 patients as it improves their anemic state and may possibly contribute to mobilizing excessive hepatic iron. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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16 pages, 966 KiB

Open AccessArticle

Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia

by Hilde van der Staaij, Albertine E. Donker, Dirk L. Bakkeren, Jan M. J. I. Salemans, Lisette A. A. Mignot-Evers, Marlies Y. Bongers, Jeanne P. Dieleman, Tessel E. Galesloot, Coby M. Laarakkers, Siem M. Klaver and Dorine W. Swinkels

Int. J. Mol. Sci. 2022, 23(3), 1917; https://doi.org/10.3390/ijms23031917 - 08 Feb 2022

Cited by 4 | Viewed by 4418

Abstract

Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation [...] Read more.

Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4–1.1%/nM) and 16.7%/nM (IQR, 12.0–24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84–100% and 91–100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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14 pages, 2381 KiB

Open AccessArticle

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

by Barbara Eleni Rosato, Roberta Marra, Vanessa D’Onofrio, Federica Del Giudice, Simone Della Monica, Achille Iolascon, Immacolata Andolfo and Roberta Russo

Int. J. Mol. Sci. 2022, 23(3), 1304; https://doi.org/10.3390/ijms23031304 - 24 Jan 2022

Cited by 5 | Viewed by 3217

Abstract

Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the [...] Read more.

Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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29 pages, 5252 KiB

Open AccessArticle

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer’s, and Parkinson’s Diseases

by Animesh Alexander Raha, Anwesha Biswas, James Henderson, Subhojit Chakraborty, Anthony Holland, Robert P. Friedland, Elizabeta Mukaetova-Ladinska, Shahid Zaman and Ruma Raha-Chowdhury

Int. J. Mol. Sci. 2022, 23(3), 1060; https://doi.org/10.3390/ijms23031060 - 19 Jan 2022

Cited by 22 | Viewed by 3682

Abstract

Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The [...] Read more.

Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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18 pages, 3600 KiB

Open AccessArticle

H-Ferritin Produced by Myeloid Cells Is Released to the Circulation and Plays a Major Role in Liver Iron Distribution during Infection

by Ana C. Moreira, Tânia Silva, Gonçalo Mesquita, Ana Cordeiro Gomes, Clara M. Bento, João V. Neves, Daniela F. Rodrigues, Pedro N. Rodrigues, Agostinho A. Almeida, Paolo Santambrogio and Maria Salomé Gomes

Int. J. Mol. Sci. 2022, 23(1), 269; https://doi.org/10.3390/ijms23010269 - 27 Dec 2021

Cited by 8 | Viewed by 2988

Abstract

During infections, the host redistributes iron in order to starve pathogens from this nutrient. Several proteins are involved in iron absorption, transport, and storage. Ferritin is the most important iron storage protein. It is composed of variable proportions of two peptides, the L- [...] Read more.

During infections, the host redistributes iron in order to starve pathogens from this nutrient. Several proteins are involved in iron absorption, transport, and storage. Ferritin is the most important iron storage protein. It is composed of variable proportions of two peptides, the L- and H-ferritins (FTL and FTH). We previously showed that macrophages increase their expression of FTH1 when they are infected in vitro with Mycobacterium avium, without a significant increase in FTL. In this work, we investigated the role of macrophage FTH1 in M. avium infection in vivo. We found that mice deficient in FTH1 in myeloid cells are more resistant to M. avium infection, presenting lower bacterial loads and lower levels of proinflammatory cytokines than wild-type littermates, due to the lower levels of available iron in the tissues. Importantly, we also found that FTH1 produced by myeloid cells in response to infection may be found in circulation and that it plays a key role in iron redistribution. Specifically, in the absence of FTH1 in myeloid cells, increased expression of ferroportin is observed in liver granulomas and increased iron accumulation occurs in hepatocytes. These results highlight the importance of FTH1 expression in myeloid cells for iron redistribution during infection. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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14 pages, 1807 KiB

Open AccessArticle

Effect of Erythropoietin on the Expression of Murine Transferrin Receptor 2

by Betty Berezovsky, Martin Báječný, Jana Frýdlová, Iuliia Gurieva, Daniel Wayne Rogalsky, Petr Přikryl, Vít Pospíšil, Emanuel Nečas, Martin Vokurka and Jan Krijt

Int. J. Mol. Sci. 2021, 22(15), 8209; https://doi.org/10.3390/ijms22158209 - 30 Jul 2021

Cited by 4 | Viewed by 2124

Abstract

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose [...] Read more.

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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14 pages, 4887 KiB

Open AccessArticle

Structural Insights for the Stronger Ability of Shrimp Ferritin to Coordinate with Heavy Metal Ions as Compared to Human H-Chain Ferritin

by Yingjie Wang, Jiachen Zang, Chengtao Wang, Xiuqing Zhang and Guanghua Zhao

Int. J. Mol. Sci. 2021, 22(15), 7859; https://doi.org/10.3390/ijms22157859 - 23 Jul 2021

Cited by 11 | Viewed by 2418

Abstract

Although apoferritin has been widely utilized as a new class of natural protein nanovehicles for encapsulation and delivery of nutraceuticals, its ability to remove metal heavy ions has yet to be explored. In this study, for the first time, we demonstrated that the [...] Read more.

Although apoferritin has been widely utilized as a new class of natural protein nanovehicles for encapsulation and delivery of nutraceuticals, its ability to remove metal heavy ions has yet to be explored. In this study, for the first time, we demonstrated that the ferritin from kuruma prawns (Marsupenaeus japonicus), named MjF, has a pronouncedly larger ability to resist denaturation induced by Cd²⁺ and Hg²⁺ as compared to its analogue, human H-chain ferritin (HuHF), despite the fact that these two proteins share a high similarity in protein structure. Treatment of HuHF with Cd²⁺ or Hg²⁺ at a metal ion/protein shell ratio of 100/1 resulted in marked protein aggregation, while the MjF solution was kept constantly clear upon treatment with Cd²⁺ and Hg²⁺ at different protein shell/metal ion ratios (50/1, 100/1, 250/1, 500/1, 1000/1, and 2500/1). Structural comparison analyses in conjunction with the newly solved crystal structure of the complex of MjF plus Cd²⁺ or Hg²⁺ revealed that cysteine (Cys) is a major residue responsible for such binding, and that the large difference in the ability to resist denaturation induced by these two heavy metal ions between MjF and HuHF is mainly derived from the different positions of Cys residues in these two proteins; namely, Cys residues in HuHF are located on the outer surface, while Cys residues from MjF are buried within the protein shell. All of these findings raise the high possibility that prawn ferritin, as a food-derived protein, could be developed into a novel bio-template to remove heavy metal ions from contaminated food systems. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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Review

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18 pages, 1513 KiB

Open AccessReview

Iron, Neuroinflammation and Neurodegeneration

by Roberta J. Ward, David T. Dexter and Robert R. Crichton

Int. J. Mol. Sci. 2022, 23(13), 7267; https://doi.org/10.3390/ijms23137267 - 30 Jun 2022

Cited by 44 | Viewed by 4515

Abstract

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will [...] Read more.

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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12 pages, 841 KiB

Open AccessReview

Iron Mining for Erythropoiesis

by Margherita Correnti, Elena Gammella, Gaetano Cairo and Stefania Recalcati

Int. J. Mol. Sci. 2022, 23(10), 5341; https://doi.org/10.3390/ijms23105341 - 10 May 2022

Cited by 7 | Viewed by 4754

Abstract

Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required [...] Read more.

Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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16 pages, 693 KiB

Open AccessReview

Iron Homeostasis in the CNS: An Overview of the Pathological Consequences of Iron Metabolism Disruption

by Christina A. Porras and Tracey A. Rouault

Int. J. Mol. Sci. 2022, 23(9), 4490; https://doi.org/10.3390/ijms23094490 - 19 Apr 2022

Cited by 10 | Viewed by 3002

Abstract

Iron homeostasis disruption has increasingly been implicated in various neurological disorders. In this review, we present an overview of our current understanding of iron metabolism in the central nervous system. We examine the consequences of both iron accumulation and deficiency in various disease [...] Read more.

Iron homeostasis disruption has increasingly been implicated in various neurological disorders. In this review, we present an overview of our current understanding of iron metabolism in the central nervous system. We examine the consequences of both iron accumulation and deficiency in various disease contexts including neurodegenerative, neurodevelopmental, and neuropsychological disorders. The history of animal models of iron metabolism misregulation is also discussed followed by a comparison of three patients with a newly discovered neurodegenerative disorder caused by mutations in iron regulatory protein 2. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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21 pages, 2322 KiB

Open AccessReview

Iron Metabolism in Aging and Age-Related Diseases

by Yao Tian, Yuanliangzi Tian, Zhixiao Yuan, Yutian Zeng, Shuai Wang, Xiaolan Fan, Deying Yang and Mingyao Yang

Int. J. Mol. Sci. 2022, 23(7), 3612; https://doi.org/10.3390/ijms23073612 - 25 Mar 2022

Cited by 27 | Viewed by 5613

Abstract

Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic [...] Read more.

Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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16 pages, 689 KiB

Open AccessReview

The Impact of Iron Chelators on the Biology of Cancer Stem Cells

by Julia Szymonik, Kamila Wala, Tomasz Górnicki, Jolanta Saczko, Bartosz Pencakowski and Julita Kulbacka

Int. J. Mol. Sci. 2022, 23(1), 89; https://doi.org/10.3390/ijms23010089 - 22 Dec 2021

Cited by 14 | Viewed by 2980

Abstract

Neoplastic diseases are still a major medical challenge, requiring a constant search for new therapeutic options. A serious problem of many cancers is resistance to anticancer drugs and disease progression in metastases or local recurrence. These characteristics of cancer cells may be related [...] Read more.

Neoplastic diseases are still a major medical challenge, requiring a constant search for new therapeutic options. A serious problem of many cancers is resistance to anticancer drugs and disease progression in metastases or local recurrence. These characteristics of cancer cells may be related to the specific properties of cancer stem cells (CSC). CSCs are involved in inhibiting cells’ maturation, which is essential for maintaining their self-renewal capacity and pluripotency. They show increased expression of transcription factor proteins, which were defined as stemness-related markers. This group of proteins includes OCT4, SOX2, KLF4, Nanog, and SALL4. It has been noticed that the metabolism of cancer cells is changed, and the demand for iron is significantly increased. Iron chelators have been proven to have antitumor activity and influence the expression of stemness-related markers, thus reducing chemoresistance and the risk of tumor cell progression. This prompts further investigation of these agents as promising anticancer novel drugs. The article presents the characteristics of stemness markers and their influence on the development and course of neoplastic disease. Available iron chelators were also described, and their effects on cancer cells and expression of stemness-related markers were analyzed. Full article

(This article belongs to the Special Issue New Advances in Iron Metabolism, Ferritin and Hepcidin Research)

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