Modulation of Cellular Iron Metabolism by Hydrogen Peroxide

Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs. The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H2O2 that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 μmH2O2 for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H2O2induces a ∼4-fold increase in TfR mRNA levels within 2–6 h, and subsequent accumulation of newly synthesized protein after 4 h. This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells. Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the DivalentMetal Transporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs. Finally, H2O2-treated cells display an increased capacity to sequester 59Fe in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of59Fe intracellular distribution. Our data suggest that H2O2 regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.

• Publication year

  2001

• Venue

  Journal of Biological Chemistry

• Publication date

  2001-06-08

• Fields of study

  Biology, Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1074/jbc.M100245200PMID 11264285
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter

  2000cited by this paper
• A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.

  2000cited by this paper
• Nitric Oxide, Oxygen Radicals, and Iron Metabolism

  2000cited by this paper
• Translational control of gene expression

  2000cited by this paper
• A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism*

  2000cited by this paper
• Iron regulatory proteins and the molecular control of mammalian iron metabolism.

  2000cited by this paper
• Nitric Oxide, Oxidative Stress, and Signal Transduction

  2000cited by this paper
• Combinatorial mRNA Regulation: Iron Regulatory Proteins and Iso-iron-responsive Elements (Iso-IREs)*

  2000cited by this paper
• Iron regulatory proteins in pathobiology.

  2000cited by this paper
• Heterologous expression, functional characterization and localization of two isoforms of the monkey iron transporter Nramp2.

  2000cited by this paper
• Coordinate Transcriptional and Translational Regulation of Ferritin in Response to Oxidative Stress

  2000cited by this paper
• Iron metabolism.

  1999cited by this paper
• Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species.

  1999cited by this paper
• Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide-dependent and -independent pathways following activation with gamma interferon and lipopolysaccharide.

  1999cited by this paper
• Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis.

  1999cited by this paper
• The effect of intracellular iron concentration and nitrogen monoxide on Nramp2 expression and non-transferrin-bound iron uptake.

  1999cited by this paper
• Human Cytoplasmic Aconitase (Iron Regulatory Protein 1) Is Converted into Its [3Fe-4S] Form by Hydrogen Peroxide in Vitro but Is Not Activated for Iron-responsive Element Binding*

  1999cited by this paper
• Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1.

  1999cited by this paper
• Disorders of iron metabolism.

  1999cited by this paper
• Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation.

  1999cited by this paper
• Activation of iron regulatory protein-1 by oxidative stress in vitro.

  1998cited by this paper
• Oxygen radicals and signaling.

  1998cited by this paper
• Localized Unfolding at the Junction of Three Ferritin Subunits

  1998cited by this paper
• IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F.

  1998cited by this paper
• Loops and Bulge/Loops in Iron-responsive Element Isoforms Influence Iron Regulatory Protein Binding

  1998cited by this paper
• Function and regulation of transferrin and ferritin.

  1998cited by this paper
• Iron Differentially Stimulates Translation of Mitochondrial Aconitase and Ferritin mRNAs in Mammalian Cells

  1998cited by this paper
• Oxidative stress leads to a rapid alteration of transferrin receptor intravesicular trafficking.

  1998cited by this paper
• Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene

  1997cited by this paper
• Waiting for frataxin

  1997cited by this paper
• Cloning and characterization of a mammalian proton-coupled metal-ion transporter

  1997cited by this paper
• Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells.

  1997cited by this paper
• Complex regulation of transferrin receptors during erythropoietin-induced differentiation of J2E erythroid cells--elevated transcription and mRNA stabilisation produce only a modest rise in protein content.

  1997cited by this paper
• Biochemical and Molecular Roles of Nutrients Dietary Iron Intake Modulates the Activity of Iron Regulatory Proteins and the Abundance of Ferritin and Mitochondrial Aconitase in Rat Liver

  1997cited by this paper
• Managed care for viruses

  1997cited by this paper
• Differences in the Regulation of Iron Regulatory Protein-1 (IRP-1) by Extra- and Intracellular Oxidative Stress*

  1997cited by this paper
• Regulation of cellular iron metabolism by erythropoietin: activation of iron-regulatory protein and upregulation of transferrin receptor expression in erythroid cells.

  1997cited by this paper
• Functional antioxidant responsive elements.

  1997cited by this paper
• Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways

  1996cited by this paper
• Identification of a Conserved and Functional Iron-responsive Element in the 5′-Untranslated Region of Mammalian Mitochondrial Aconitase*

  1996cited by this paper
• Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements.

  1996cited by this paper
• Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress.

  1996cited by this paper
• Identification and characterization of a second mouse Nramp gene.

  1995cited by this paper
• Oxidative stress induces activation of a cytosolic protein responsible for control of iron uptake.

  1995cited by this paper
• Succinate Dehydrogenase b mRNA of Drosophila melanogaster Has a Functional Iron-responsive Element in Its 5′-Untranslated Region (*)

  1995cited by this paper
• Induction of Ferritin Synthesis by Oxidative Stress

  1995cited by this paper
• Rapid responses to oxidative stress mediated by iron regulatory protein.

  1995cited by this paper
• Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 3′ UTR and does not involve poly(A) tail shortening.

  1994cited by this paper
• Regulation of transferrin receptor mRNA expression. Distinct regulatory features in erythroid cells.

  1994cited by this paper
• Menadione-induced oxidative stress leads to a rapid down-modulation of transferrin receptor recycling.

  1993cited by this paper
• Translational control of 5-aminolevulinate synthase mRNA by iron-responsive elements in erythroid cells.

  1993cited by this paper
• Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin.

  1993cited by this paper
• Ferritin: a cytoprotective antioxidant strategem of endothelium.

  1992cited by this paper
• Role of free radicals and catalytic metal ions in human disease: an overview.

  1990cited by this paper
• Iron regulation of transferrin receptor mRNA levels requires iron‐responsive elements and a rapid turnover determinant in the 3′ untranslated region of the mRNA.

  1989cited by this paper
• Cell-specific properties of red cell and liver ferritin from bullfrog tadpoles probed by phosphorylation in vitro.

  1984cited by this paper

• Selenoprotein K Confers Protection against Iron Dyshomeostasis-Related Neurotoxicity by Regulating the Palmitoylation of TfR‑1

  2025cites this paper
• Iron Chelation Reduces Intracellular Hydroxyl Radicals in Normal Human Dermal Fibroblasts Independently of Aging

  2025cites this paper
• Involvement of endolysosome iron in HIV-1 gp120-, morphine-, and iron supplementation-induced disruption of the reactive species interactome and induction of neurotoxicity

  2025cites this paper
• On the Chemical and Biological Characteristics of Multifunctional Compounds for the Treatment of Parkinson’s Disease

  2023cites this paper
• The Effects of the Action of Chromium, Aluminum, Nickel and Iron on Human Fibroblast and Stem Cell Cultures

  2022cites this paper
• Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice

  2022cites this paper
• Chinese hamster V79 cells’ dependence on background ionizing radiation for optimal growth

  2021cites this paper
• Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

  2021cites this paper
• Biological mechanisms of reactive oxygen species (ROS)

  2020cites this paper
• Therapeutic Targeting of SDHB-Mutated Pheochromocytoma/Paraganglioma with Pharmacologic Ascorbic Acid

  2020cites this paper
• Sources of Oxidants and Function of ROS Inside the Macromolecule Cells

  2020cites this paper
• Antioxidant Therapeutic Defenses Toward Redox Biology and Oxidative Stress

  2020cites this paper
• Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers

  2020cites this paper
• Vitamin C and Cell Death

  2020cites this paper
• Effects of interactions between antioxidant defense therapy and ROS

  2020cites this paper
• Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load.

  2019cites this paper
• Iron homeostasis and oxidative stress: An intimate relationship.

  2019cites this paper
• Pharmacological Ascorbate as a Means of Sensitizing Cancer Cells to Radio-Chemotherapy While Protecting Normal Tissue.

  2019cites this paper
• First report on transferrin in the silkworm, Antheraea mylitta, with a putative role in antioxidant defense: Insights from proteomic analysis and immunodetection.

  2019cites this paper
• Noxious Iron–Calcium Connections in Neurodegeneration

  2019cites this paper
• The role of redox-active iron metabolism in the selective toxicity of pharmacological ascorbate in cancer therapy

  2018influential citation
• Could Alzheimer’s Disease Originate in the Periphery and If So How So?

  2018cites this paper
• O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.

  2017cites this paper
• Mitochondrial Ferritin Protects Hydrogen Peroxide-Induced Neuronal Cell Damage

  2017cites this paper
• Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events.

  2017cites this paper
• Concentration Does Matter: The Beneficial and Potentially Harmful Effects of Ascorbate in Humans and Plants

  2017cites this paper
• O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.

  2017cites this paper
• Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases

  2017cites this paper
• Exposure of aconitase to smoking-related oxidants results in iron loss and increased iron response protein-1 activity: potential mechanisms for iron accumulation in human arterial cells

  2016cites this paper
• Intracellular labile iron determines H2O2-induced apoptotic signaling via sustained activation of ASK1/JNK-p38 axis.

  2016cites this paper
• Catecholamine Stress Hormones Regulate Cellular Iron Homeostasis by a Posttranscriptional Mechanism Mediated by Iron Regulatory Protein

  2015cites this paper
• Oxidative Stress and the Homeodynamics of Iron Metabolism

  2015cites this paper
• Are Reactive Oxygen Species Always Detrimental to Pathogens?

  2014cites this paper
• Régulation de l'hepcidine et le rôle de la lipocaline 2 dans l'homéostasie du fer / Novel insights into the regulation of hepcidin and the role of lipocalin 2 in iron homeostasis

  2014cites this paper
• Oxidative stress and hepatic Nox proteins in chronic hepatitis C and hepatocellular carcinoma.

  2014cites this paper
• Cereal grass pulvini: agronomically significant models for studying gravitropism signaling and tissue polarity.

  2013cites this paper
• The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.

  2013cites this paper
• Mammalian Iron Homeostasis in Health and Disease: Uptake, Storage, Transport, and Molecular Mechanisms of Action

  2013cites this paper
• Regulation of iron transport and the role of transferrin.

  2012cites this paper
• Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling.

  2012cites this paper
• Molecular and functional characterization of ferritin in abalone Haliotis diversicolor supertexta

  2012influential citation
• Iron and the Reticuloendothelial System

  2012cites this paper
• Cellular Iron Metabolism – The IRP/IRE Regulatory Network

  2012cites this paper
• Regulation of cellular iron metabolism

  2011cites this paper
• Regulation of cellular iron metabolism

  2011cites this paper
• Comparison of changes in gene expression of transferrin receptor-1 and other iron-regulatory proteins in rat liver and brain during acute-phase response

  2011cites this paper
• Iron sensing and signalling

  2011cites this paper
• Intralysosomal iron induces lysosomal membrane permeabilization and cathepsin D-mediated cell death in trabecular meshwork cells exposed to oxidative stress.

  2010cites this paper
• Corticosterone Induces Dysregulation of Iron Metabolism in Hippocampal Neurons In Vitro

  2010cites this paper
• Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

  2010cites this paper
• Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases.

  2009cites this paper
• Overexpression of Mitochondrial Ferritin Sensitizes Cells to Oxidative Stress Via an Iron-Mediated Mechanism

  2009cites this paper
• The mixture of procyanidins extracted from the lotus seed pod and bilobalide ameliorates scopolamine-induced memory impairment in mice

  2009cites this paper
• Reactive Oxygen Species Regulate Ceruloplasmin by a Novel mRNA Decay Mechanism Involving Its 3′-Untranslated Region

  2009cites this paper
• Role of iron in the pathogenesis of cysteamine-induced duodenal ulceration in rats.

  2009cites this paper
• Iron metabolism in the anemia of chronic disease.

  2009cites this paper
• The mixture of procyanidins extracted from the lotus seed pod and bilobalide ameliorates scopolamine-induced memory impairment in mice

  2009cites this paper
• Glutathione depletion in immortalized midbrain-derived dopaminergic neurons results in increases in the labile iron pool: implications for Parkinson's disease.

  2009cites this paper
• Psychological stress induces dysregulation of iron metabolism in rat brain.

  2008cites this paper
• Human Nbp35 Is Essential for both Cytosolic Iron-Sulfur Protein Assembly and Iron Homeostasis

  2008cites this paper
• Oxidative Stress and Iron Homeostasis: Mechanistic and Health Aspects

  2008cites this paper
• Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

  2008cites this paper
• Oxidative stress and iron homeostasis: mechanistic and health aspects.

  2008cites this paper
• Zinc Deficiency-induced Iron Accumulation, a Consequence of Alterations in Iron Regulatory Protein-binding Activity, Iron Transporters, and Iron Storage Proteins*

  2008cites this paper
• Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network*

  2007cites this paper
• Targeted alterations in iron homeostasis underlie plant defense responses

  2007cites this paper
• Iron-regulatory proteins: molecular biology and pathophysiological implications

  2007cites this paper
• Iron and reactive oxygen in wheat-pathogen interactions

  2007cites this paper
• Increased levels of reactive oxygen species and expression of a cytoplasmic aconitase/iron regulatory protein 1 homolog during the early response of maize pulvini to gravistimulation.

  2007cites this paper
• Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells.

  2007cites this paper
• Redox regulation of hepatitis C in nonalcoholic and alcoholic liver.

  2007cites this paper
• Cloning and expression of an alpha-amylase gene from Phanerochaete chrysosporium.

  2007cites this paper
• Cloning and Expression of an α-Amylase Gene from Phanerochaete chrysosporium

  2007cites this paper
• Oxidative stress disrupts internalization and endocytic trafficking of transferrin in a human malignant keratinocyte line

  2007cites this paper
• Liver-homing of purified glucose oxidase: a novel in vivo model of physiological hepatic oxidative stress (H2O2).

  2007cites this paper
• Excess Capacity of the Iron Regulatory Protein System*

  2007cites this paper
• Ferritin levels in microglia depend upon activation: modulation by reactive oxygen species.

  2006cites this paper
• The role of iron regulatory proteins in mammalian iron homeostasis and disease

  2006cites this paper
• Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis.

  2006cites this paper
• Superoxide dismutase 1 modulates expression of transferrin receptor

  2006cites this paper
• Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis.

  2006cites this paper
• Development in Patients with Alcohol-Induced Cirrhosis Hepatic Iron Accumulation and Hepatocellular Carcinoma Genetic Polymorphisms in Antioxidant Enzymes Modulate

  2006cites this paper
• Intracellular chemiluminescence activates targeted photodynamic destruction of leukaemic cells

  2006cites this paper
• Hepcidin generated by hepatoma cells inhibits iron export from co-cultured THP1 monocytes.

  2006cites this paper
• Iron chelators reduce chromosomal breaks in ataxia-telangiectasia cells.

  2006cites this paper
• Free radicals act as effectors in the growth inhibition and apoptosis of iron-treated Burkitt's lymphoma cells

  2006cites this paper
• Dynamic modeling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson's disease.

  2006cites this paper
• Effects of vitamin c on dna damage, iron homeostasis and gene expression profiling in human fibroblasts

  2006cites this paper
• Hepcidin generated by hepatoma cells inhibits iron export from co-cultured THP1 monocytes *

  2006cites this paper
• Loss of the von Hippel Lindau Tumor Suppressor Disrupts Iron Homeostasis in Renal Carcinoma Cells*

  2005cites this paper
• Extracellular H2O2 and not superoxide determines the compartment-specific activation of transferrin receptor by iron regulatory protein 1

  2005cites this paper
• Iron regulatory protein 1 as a sensor of reactive oxygen species

  2005cites this paper
• Oxidation-induced ferritin turnover in microglial cells: role of proteasome.

  2005cites this paper
• Down-regulation of Iron Regulatory Protein 1 Activities and Expression in Superoxide Dismutase 1 Knock-out Mice Is Not Associated with Alterations in Iron Metabolism*

  2005cites this paper
• Iron Metabolism and the IRE/IRP Regulatory System: An Update

  2004cites this paper
• Defective regulation of iron transporters leading to iron excess in the polymorphonuclear leukocytes of patients on maintenance hemodialysis.

  2004cites this paper
• Modulation of DMT1 Activity by Redox Compounds

  2004cites this paper
• Antioxidant diet supplementation influences blood iron status in endurance athletes.

  2004cites this paper
• Rat duodenal IRP1 activity and iron absorption in iron deficiency and after H2O2 perfusion

  2004cites this paper
• Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis

  2004cites this paper