Iron Metabolism in Oligodendrocytes and Astrocytes, Implications for Myelination and Remyelination

Iron is a key nutrient for normal central nervous system (CNS) development and function; thus, iron deficiency as well as iron excess may result in harmful effects in the CNS. Oligodendrocytes and astrocytes are crucial players in brain iron equilibrium. However, the mechanisms of iron uptake, storage, and efflux in oligodendrocytes and astrocytes during CNS development or under pathological situations such as demyelination are not completely understood. In the CNS, iron is directly required for myelin production as a cofactor for enzymes involved in ATP, cholesterol and lipid synthesis, and oligodendrocytes are the cells with the highest iron levels in the brain which is linked to their elevated metabolic needs associated with the process of myelination. Unlike oligodendrocytes, astrocytes do not have a high metabolic requirement for iron. However, these cells are in close contact with blood vessel and have a strong iron transport capacity. In several pathological situations, changes in iron homoeostasis result in altered cellular iron distribution and accumulation and oxidative stress. In inflammatory demyelinating diseases such as multiple sclerosis, reactive astrocytes accumulate iron and upregulate iron efflux and influx molecules, which suggest that they are outfitted to take up and safely recycle iron. In this review, we will discuss the participation of oligodendrocytes and astrocytes in CNS iron homeostasis. Understanding the molecular mechanisms of iron uptake, storage, and efflux in oligodendrocytes and astrocytes is necessary for planning effective strategies for iron management during CNS development as well as for the treatment of demyelinating diseases.

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CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH

Neuro-Oncology ◽

10.1093/neuonc/noaa215.070 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii17-ii17

Author(s):

Katie Troike ◽

Erin Mulkearns-Hubert ◽

Daniel Silver ◽

James Connor ◽

Justin Lathia

Keyword(s):

Tumor Cells ◽

Iron Uptake ◽

Iron Homeostasis ◽

Iron Status ◽

Tumor Grade ◽

Hfe Gene ◽

Iron Release ◽

Female Patients ◽

Cellular Iron

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.

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Iron homeostasis: new tales from the crypt

Blood ◽

10.1182/blood.v96.13.4020 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4020-4027 ◽

Cited By ~ 106

Author(s):

Cindy N. Roy ◽

Caroline A. Enns

Keyword(s):

Iron Uptake ◽

Iron Transport ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Hereditary Hemochromatosis ◽

The Body ◽

Regulatory Proteins ◽

Iron Regulatory Proteins ◽

Duodenal Epithelium ◽

Related Proteins

Abstract The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

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Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection

Journal of Experimental Medicine ◽

10.1084/jem.20121946 ◽

2013 ◽

Vol 210 (5) ◽

pp. 855-873 ◽

Cited By ~ 109

Author(s):

Manfred Nairz ◽

Ulrike Schleicher ◽

Andrea Schroll ◽

Thomas Sonnweber ◽

Igor Theurl ◽

...

Keyword(s):

Nitric Oxide ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Acquisition ◽

Iron Chelator ◽

Related Factor ◽

Cellular Iron ◽

Splenic Macrophages ◽

Ferroportin 1 ◽

Pathogen Control

Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2−/− macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2−/− macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2−/− macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages

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Mechanisms of Mitochondrial Iron-Sulfur Protein Biogenesis

Annual Review of Biochemistry ◽

10.1146/annurev-biochem-013118-111540 ◽

2020 ◽

Vol 89 (1) ◽

pp. 471-499 ◽

Cited By ~ 28

Author(s):

Roland Lill ◽

Sven-A. Freibert

Keyword(s):

Molecular Mechanisms ◽

De Novo ◽

Lipid Synthesis ◽

Cluster Assembly ◽

Iron Sulfur Cluster ◽

Atp Production ◽

Cellular Iron ◽

Iron Sulfur ◽

Sulfur Protein ◽

S Proteins

Mitochondria are essential in most eukaryotes and are involved in numerous biological functions including ATP production, cofactor biosyntheses, apoptosis, lipid synthesis, and steroid metabolism. Work over the past two decades has uncovered the biogenesis of cellular iron-sulfur (Fe/S) proteins as the essential and minimal function of mitochondria. This process is catalyzed by the bacteria-derived iron-sulfur cluster assembly (ISC) machinery and has been dissected into three major steps: de novo synthesis of a [2Fe-2S] cluster on a scaffold protein; Hsp70 chaperone–mediated trafficking of the cluster and insertion into [2Fe-2S] target apoproteins; and catalytic conversion of the [2Fe-2S] into a [4Fe-4S] cluster and subsequent insertion into recipient apoproteins. ISC components of the first two steps are also required for biogenesis of numerous essential cytosolic and nuclear Fe/S proteins, explaining the essentiality of mitochondria. This review summarizes the molecular mechanisms underlying the ISC protein–mediated maturation of mitochondrial Fe/S proteins and the importance for human disease.

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HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽

10.1182/blood.v94.11.3915.423k27_3915_3921 ◽

1999 ◽

Vol 94 (11) ◽

pp. 3915-3921 ◽

Cited By ~ 2

Author(s):

H.D. Riedel ◽

M.U. Muckenthaler ◽

S.G. Gehrke ◽

I. Mohr ◽

K. Brennan ◽

...

Keyword(s):

Transferrin Receptor ◽

Iron Uptake ◽

Iron Homeostasis ◽

Hereditary Hemochromatosis ◽

Regulatory Protein ◽

Intracellular Iron ◽

Iron Storage ◽

Iron Regulatory Proteins ◽

Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

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Iron homeostasis: new tales from the crypt

Blood ◽

10.1182/blood.v96.13.4020.h8004020_4020_4027 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4020-4027 ◽

Cited By ~ 1

Author(s):

Cindy N. Roy ◽

Caroline A. Enns

Keyword(s):

Iron Uptake ◽

Iron Transport ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Hereditary Hemochromatosis ◽

The Body ◽

Regulatory Proteins ◽

Iron Regulatory Proteins ◽

Duodenal Epithelium ◽

Related Proteins

The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

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Molecular mechanisms of iron uptake in eukaryotes

Physiological Reviews ◽

10.1152/physrev.1996.76.1.31 ◽

1996 ◽

Vol 76 (1) ◽

pp. 31-47 ◽

Cited By ~ 130

Author(s):

D. M. de Silva ◽

C. C. Askwith ◽

J. Kaplan

Keyword(s):

Iron Uptake ◽

Mammalian Cells ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Acquisition ◽

Genetic Disorders ◽

Essential Element ◽

Recent Developments

Iron serves essential functions in both prokaryotes and eukaryotes, and cells have highly specialized mechanisms for acquiring and handling this metal. The primary mechanism by which the concentration of iron in biologic systems is controlled is through the regulation of iron uptake. Although the role of transferrin in mammalian iron homeostasis has been well characterized, the study of genetic disorders of iron metabolism has revealed other, transferrin-independent, mechanisms by which cells can acquire iron. In an attempt to understand how eukaryotic systems take up this essential element, investigators have begun studying the simple eukaryote Saccharomyces cerevisiae. Several genes have been identified and cloned that act in concert to allow iron acquisition from the environment. Some of these genes appear to have functional homologues in human systems. This review focuses on the recent developments in understanding eukaryotic iron uptake with an emphasis on the genetic and molecular characterization of these systems in both cultured mammalian cells and S. cerevisiae. An unexpected connection between iron and copper homeostasis has been revealed by recent genetic studies, which confirm biologic observations made several decades ago.

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Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis

Blood ◽

10.1182/blood-2010-09-307462 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1379-1389 ◽

Cited By ~ 31

Author(s):

Pedro Ramos ◽

Ella Guy ◽

Nan Chen ◽

Catia C. Proenca ◽

Sara Gardenghi ◽

...

Keyword(s):

Iron Overload ◽

Iron Uptake ◽

Iron Homeostasis ◽

Hereditary Hemochromatosis ◽

Dietary Iron ◽

Erythroid Cells ◽

Hepcidin Expression ◽

Stress Erythropoiesis ◽

Cellular Iron ◽

Cellular Iron Uptake

Abstract In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis.

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The transferrin receptor: the cellular iron gate

Metallomics ◽

10.1039/c7mt00143f ◽

2017 ◽

Vol 9 (10) ◽

pp. 1367-1375 ◽

Cited By ~ 47

Author(s):

Elena Gammella ◽

Paolo Buratti ◽

Gaetano Cairo ◽

Stefania Recalcati

Keyword(s):

Transferrin Receptor ◽

Iron Uptake ◽

Iron Homeostasis ◽

Cellular Iron ◽

Iron Gate ◽

Cellular Iron Uptake

The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron homeostasis.

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Molecular mechanisms of normal iron homeostasis

Hematology ◽

10.1182/asheducation-2009.1.207 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 207-214 ◽

Cited By ~ 70

Author(s):

An-Sheng Zhang ◽

Caroline A. Enns

Keyword(s):

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Absorption ◽

Hypoxia Inducible Factor ◽

Bmp Signaling ◽

Control Mechanisms ◽

Iron Regulatory Proteins ◽

Hepcidin Expression ◽

Cellular Iron ◽

Morphogenetic Protein

Abstract Humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Dietary iron absorption is regulated locally by hypoxia inducible factor (HIF) signaling and iron-regulatory proteins (IRPs) in enterocytes and systematically by hepatic hepcidin, the central iron regulatory hormone. Hepcidin not only controls the rate of iron absorption but also determines iron mobilization from stores through negatively modulating the function of ferroportin, the only identified cellular iron exporter to date. The regulation of hepatic hepcidin is accomplished by the coordinated activity of multiple proteins through different signaling pathways. Recent studies have greatly expanded the knowledge in the understanding of hepcidin expression and regulation by the bone morphogenetic protein (BMP) signaling, the erythroid factors, and inflammation. In this review, we mainly focus on the roles of recently identified proteins in the regulation of iron homeostasis.

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