1. Biochemistry and Chemical Biology
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Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients

  1. Andrew Melber
  2. Un Na
  3. Ajay Vashisht
  4. Benjamin D Weiler
  5. Roland Lill
  6. James A Wohlschlegel
  7. Dennis R Winge  Is a corresponding author
  1. University of Utah Health Sciences Center, United States
  2. David Geffen School of Medicine at UCLA, United States
  3. Philipps-Universität Marburg, Germany
Research Article
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Cite this article as: eLife 2016;5:e15991 doi: 10.7554/eLife.15991
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Abstract

Iron-sulfur (Fe-S) clusters are essential for many cellular processes, ranging from aerobic respiration, metabolite biosynthesis, ribosome assembly and DNA repair. Mutations in NFU1 and BOLA3 have been linked to genetic diseases with defects in mitochondrial Fe-S centers. Through genetic studies in yeast, we demonstrate that Nfu1 functions in a late step of [4Fe-4S] cluster biogenesis that is of heightened importance during oxidative metabolism. Proteomic studies revealed Nfu1 physical interacts with components of the ISA [4Fe-4S] assembly complex and client proteins that need [4Fe-4S] clusters to function. Additional studies focused on the mitochondrial BolA proteins, Bol1 and Bol3 (yeast homolog to human BOLA3), revealing that Bol1 functions earlier in Fe-S biogenesis with the monothiol glutaredoxin, Grx5, and Bol3 functions late with Nfu1. Given these observations, we propose that Nfu1, assisted by Bol3, functions to facilitate Fe-S transfer from the biosynthetic apparatus to the client proteins preventing oxidative damage to [4Fe-4S] clusters.

Article and author information

Author details

  1. Andrew Melber

    Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Un Na

    Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ajay Vashisht

    Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Benjamin D Weiler

    Institut für Zytobiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Roland Lill

    Institut für Zytobiologie, Philipps-Universität Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8345-6518
  6. James A Wohlschlegel

    Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dennis R Winge

    Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, United States
    For correspondence
    dennis.winge@hsc.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1160-1189

Funding

National Institutes of Health (RO1 GM110755)

  • Dennis R Winge

National Institutes of Health (R01 GM112763)

  • James A Wohlschlegel

National Institutes of Health (T32 DK007115)

  • Andrew Melber

Deutsche Forschungsgemeinschaft (SPP 1710)

  • Roland Lill

Deutsche Forschungsgemeinschaft (Spp 1927)

  • Roland Lill

National Institutes of Health (P30 CA042014)

  • Dennis R Winge

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nikolaus Pfanner, University of Freiburg, Germany

Publication history

  1. Received: March 11, 2016
  2. Accepted: August 16, 2016
  3. Accepted Manuscript published: August 17, 2016 (version 1)
  4. Version of Record published: September 7, 2016 (version 2)

Copyright

© 2016, Melber et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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