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Cited by 195Iron Metabolism and DisordersTrace Elements in HealthHemoglobin structure and function

Nitric Oxide and Oxidative Stress (H2O2) Control Mammalian Iron Metabolism by Different Pathways

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Pantopoulos, Kostas, Weiss, Günter, Hentze, Matthias W.·1996·Molecular and Cellular Biology
DOI 10.1128/mcb.16.7.3781PMC PMC231374
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Abstract

Several cellular mRNAs are regulated posttranscriptionally by iron-responsive elements (IREs) and the cytosolic IRE-binding proteins IRP-1 and IRP-2. Three different signals are known to elicit IRP-1 activity and thus regulate IRE-containing mRNAs: iron deficiency, nitric oxide (NO), and the reactive oxygen intermediate hydrogen peroxide (H2O2). In this report, we characterize the pathways for IRP-1 regulation by NO and H2O2 and examine their effects on IRP-2. We show that the responses of IRP-1 and IRP-2 to NO remarkably resemble those elicited by iron deficiency: IRP-1 induction by NO and by iron deficiency is slow and posttranslational, while IRP-2 induction by these inductive signals is slow and requires de novo protein synthesis. In contrast, H2O2 induces a rapid posttranslational activation which is limited to IRP-1. Removal of the inductive signal H2O2 after < or = 15 min of treatment (induction phase) permits a complete IRP-1 activation within 60 min (execution phase) which is sustained for several hours. This contrasts with the IRP-1 activation pathway by NO and iron depletion, in which NO-releasing drugs or iron chelators need to be present during the entire activation phase. Finally, we demonstrate that biologically synthesized NO regulates the expression of IRE-containing mRNAs in target cells by passive diffusion and that oxidative stress endogenously generated by pharmacological modulation of the mitochondrial respiratory chain activates IRP-1, underscoring the physiological significance of NO and reactive oxygen intermediates as regulators of cellular iron metabolism. We discuss models to explain the activation pathways of IRP-1 and IRP-2. In particular, we suggest the possibility that NO affects iron availability rather than the iron-sulfur cluster of IRP-1.

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Crossref · 10.1128/mcb.16.7.3781

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  • IRPs sense free labile iron and control cellular iron homeostasis at the post-transcriptional level by interacting with IREs in Tfr1, Dmt1, Fpn1, FTH, and FTL mRNAs, counterbalancing fluctuations in intracellular iron.

    “IRPs sense free labile iron and control cellular iron homeostasis at the post-transcriptional level: Due to their ability to interact with iron-responsive elements (IREs) that are present in the non-coding mRNA sequences of Tfr1, Dmt1, Fpn1, FTH, and FTL chains, fluctuations in intracellular iron are promptly counterbalanced [179, 195].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [179]

  • IRPs 1 and 2 are mechanisms to maintain cytosolic iron levels.

    “One such mechanism to maintain cytosolic iron levels are the iron regulatory proteins (IRPs) 1 and 2 [5, 179, 195].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [179]

  • Once intracellular iron levels increase in macrophages, iNOS/NOS2 transcription is repressed, creating a negative feedback loop that promotes intracellular iron retention.

    “However, once intracellular Fe levels increase in Mø, iNOS/NOS2 transcription is repressed creating a negative feedback loop, which promotes intracellular Fe retention [85,111].”

    From The Iron age of host–microbe interactions (2015) · cites this paper as [111]

  • IFNγ induces iNOS/NOS2 expression via STAT transcription factors, and NO produced by iNOS/NOS2 regulates IRP binding affinities toward IRE in TfR and ferritin, inhibiting cellular iron import and intracellular retention.

    “IFNc also induces the expression of iNOS/NOS2 [78], via a mechanism regulated at a transcriptional level by the activation of the signal transducers and activators of transcription (STAT) family of transcription factors (Fig 2).As described above, the NO produced by iNOS/NOS2 regulates the binding affinities of IRP toward target IRE in genes such as transferrin receptor (TfR) and ferritin, inhibit”

    From The Iron age of host–microbe interactions (2015) · cites this paper as [111]

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Authors
Pantopoulos, K., Weiss, G., & Hentze, M. W.
Affiliations
European Molecular Biology Laboratory (DE)
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
1996-07-01
Volume
16
Issue
7
Pages
3781-3788
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.16.7.3781
PMC
PMC231374
OpenAlex
W2116347119
Cited by
195
References
50
Citations by year
2026: 1 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 1 · 2019: 2 · 2018: 2 · 2017: 1 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 3
FWCI
10.00
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
nitric oxide, hydrogen peroxide, oxidative stress, iron metabolism, iron-responsive element, post-transcriptional regulation, iron deficiency, iron-sulfur clusters, mitochondrial respiratory chain
MeSH terms
Animals, Cell Line, Cytosol, Humans, Hydrogen Peroxide, Iron, Iron-Sulfur Proteins, Mammals, Models, Biological, Nitric Oxide, Recombinant Proteins, RNA Processing, Post-Transcriptional, RNA, Messenger, Growth Hormone, Transfection, Signal Transduction, RNA-Binding Proteins, Oxidative Stress, Coculture Techniques, Nitric Oxide Synthase, Iron-Regulatory Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice

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