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Siderophore-mediated iron trafficking in humans is regulated by iron

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Abstract

Siderophores are best known as small iron binding molecules that facilitate microbial iron transport. In our previous study we identified a siderophore-like molecule in mammalian cells and found that its biogenesis is evolutionarily conserved. A member of the short chain dehydrogenase family of reductases, 3-hydroxy butyrate dehydrogenase (BDH2) catalyzes a rate-limiting step in the biogenesis of the mammalian siderophore. We have shown that depletion of the mammalian siderophore by inhibiting expression of bdh2 results in abnormal accumulation of cellular iron and mitochondrial iron deficiency. These observations suggest that the mammalian siderophore is a critical regulator of cellular iron homeostasis and facilitates mitochondrial iron import. By utilizing bioinformatics, we identified an iron-responsive element (IRE; a stem-loop structure that regulates genes expression post-transcriptionally upon binding to iron regulatory proteins or IRPs) in the 3′-untranslated region of the human BDH2 (hBDH2) gene. In cultured cells as well as in patient samples we now demonstrate that the IRE confers iron-dependent regulation on hBDH2 and binds IRPs in RNA electrophoretic mobility shift assays. In addition, we show that the hBDH2 IRE associates with IRPs in cells and that abrogation of IRPs by RNAi eliminates the iron-dependent regulation of hBDH2 mRNA. The key physiologic implication is that iron-mediated post-transcriptional regulation of hBDH2 controls mitochondrial iron homeostasis in human cells. These observations provide a new and an unanticipated mechanism by which iron regulates its intracellular trafficking.

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Acknowledgments

We thank Elizabeth Leibold, Matthias Hentze, Kostas Pantopoulos, and Susy Torti for providing reagents, Gretta Jacobs for human hemochromatosis liver sections, Joe Willis for normal human liver sections, Sebastian Mueller for providing RNA samples of normal and hemochromatosis liver, Robert Lanford for providing transformed liver cells of human and apes, and Alan Tartakoff for editorial assistance. This work is supported by K01CA113838, R01DK081395, and Case Western Reserve University start up funds to L.R.D and by PS09/00341 from Spanish Health Program (Instituto de Salud Carlos III) and RYC-2008-02352 research contract (Spanish Ministry of Science and Innovation) to M.S. L.R.D. is also a recipient of career developmental awards from March of Dimes and American Society of Hematology.

Disclosure of potential conflict of interests

The authors declare no conflict of interests related to this study.

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Authors and Affiliations

  1. Case Comprehensive Cancer Center and Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA

    Zhuoming Liu & L. Devireddy

  2. Texas Biomedical Research Institute, San Antonio, TX, 78227, USA

    Robert Lanford

  3. Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany

    Sebastian Mueller

  4. Geisinger Clinic, Weis Center for Research, Danville, PA, 17822, USA

    Glenn S. Gerhard

  5. Cancer and Iron Group, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Carretera Can Ruti, Cami de les Escoles s/n, 09816 Badalona, Barcelona, Spain

    Sara Luscieti & Mayka Sanchez

Authors
  1. Zhuoming Liu
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  2. Robert Lanford
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  3. Sebastian Mueller
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  4. Glenn S. Gerhard
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  5. Sara Luscieti
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  6. Mayka Sanchez
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  7. L. Devireddy
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Correspondence to L. Devireddy.

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Liu, Z., Lanford, R., Mueller, S. et al. Siderophore-mediated iron trafficking in humans is regulated by iron. J Mol Med 90, 1209–1221 (2012). https://doi.org/10.1007/s00109-012-0899-7

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  • DOI: https://doi.org/10.1007/s00109-012-0899-7

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