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PMID: 8643505 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 93 ·No. 10 ·1996-05-14 ·Pages 4925-30

Gray NK, Pantopoulos K, Dandekar T, Ackrell BA, Hentze MW

Abstract

The posttranscriptional control of iron uptake, storage, and utilization by iron-responsive elements (IREs) and iron regulatory proteins (IRPs) provides a molecular framework for the regulation of iron homeostasis in many animals. We have identified and characterized IREs in the mRNAs for two different mitochondrial citric acid cycle enzymes. Drosophila melanogaster IRP binds to an IRE in the 5' untranslated region of the mRNA encoding the iron-sulfur protein (Ip) subunit of succinate dehydrogenase (SDH). This interaction is developmentally regulated during Drosophila embryogenesis. In a cell-free translation system, recombinant IRP-1 imposes highly specific translational repression on a reporter mRNA bearing the SDH IRE, and the translation of SDH-Ip mRNA is iron regulated in D. melanogaster Schneider cells. In mammals, an IRE was identified in the 5' untranslated regions of mitochondrial aconitase mRNAs from two species. Recombinant IRP-1 represses aconitase synthesis with similar efficiency as ferritin IRE-controlled translation. The interaction between mammalian IRPs and the aconitase IRE is regulated by iron, nitric oxide, and oxidative stress (H2O2), indicating that these three signals can control the expression of mitochondrial aconitase mRNA. Our results identify a regulatory link between energy and iron metabolism in vertebrates and invertebrates, and suggest biological functions for the IRE/IRP regulatory system in addition to the maintenance of iron homeostasis.

MeSH Terms
Aconitate Hydratase/genetics Animals Base Sequence Binding Sites/genetics Cattle Citric Acid Cycle/genetics,physiology Conserved Sequence DNA, Complementary/genetics Drosophila melanogaster/genetics,metabolism Humans Iron/metabolism Iron Regulatory Protein 1 Iron-Regulatory Proteins Iron-Sulfur Proteins/genetics,metabolism Mitochondria/enzymology Molecular Sequence Data Nucleic Acid Conformation Protein Biosynthesis RNA, Messenger/chemistry,genetics,metabolism RNA-Binding Proteins/genetics,metabolism Swine
Chemicals
DNA, Complementary Iron-Regulatory Proteins Iron-Sulfur Proteins RNA, Messenger RNA-Binding Proteins Iron Aconitate Hydratase Iron Regulatory Protein 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Gray N K
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Pantopoulos K
Dandekar T
Ackrell B A
Hentze M W
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.93.10.4925
Published
1996-05-14
Pages
4925-30
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC39381
Subset
IM
Grants
NHLBI NIH HHS · HL16251 · United States
External Links
PubMed source DOI: 10.1073/pnas.93.10.4925 PMC Full Text View journal details
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