Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes

  1. Sara Bitar
  2. Timo Baumann
  3. Christopher Weber
  4. Majd Abusaada
  5. Liliana Rojas-Charry
  6. Patrick Ziegler
  7. Thomas Schettgen
  8. Isabella Eva Randerath
  9. Vivek Venkataramani
  10. Bernhard Michalke
  11. Eva-Maria Hanschmann
  12. Giuseppe Arena
  13. Rejko Krueger
  14. Li Zhang  Is a corresponding author
  15. Axel Methner  Is a corresponding author
  1. Johannes Gutenberg University of Mainz, Germany
  2. RWTH Aachen University, Germany
  3. University Hospital Würzburg, Germany
  4. Helmholtz Zentrum München, Germany
  5. University of Duisburg-Essen, Germany
  6. University of Luxembourg, Luxembourg

Abstract

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.

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All data generated or analysed during this study are included in the manuscript and supporting files

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Author details

  1. Sara Bitar

    Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Timo Baumann

    Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5374-380X
  3. Christopher Weber

    Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Majd Abusaada

    Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Liliana Rojas-Charry

    Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Patrick Ziegler

    Institute for Occupational, Social and Environmental Medicine, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Thomas Schettgen

    Institute for Occupational, Social and Environmental Medicine, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1256-1713
  8. Isabella Eva Randerath

    Institute for Occupational, Social and Environmental Medicine, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Vivek Venkataramani

    Comprehensive Cancer Center Mainfranke, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Bernhard Michalke

    Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, München, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Eva-Maria Hanschmann

    Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Giuseppe Arena

    Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2398-5503
  13. Rejko Krueger

    Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
    Competing interests
    The authors declare that no competing interests exist.
  14. Li Zhang

    Institute for Molecular Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany
    For correspondence
    lizhang2017deu@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6339-6087
  15. Axel Methner

    Department of Neurology, Johannes Gutenberg University of Mainz, Mainz, Germany
    For correspondence
    axel.methner@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8774-0057

Funding

Deutsche Forschungsgemeinschaft (445683311)

  • Axel Methner

Deutsche Forschungsgemeinschaft (461705066)

  • Vivek Venkataramani

Fonds National de la Recherche Luxembourg (C21/BM/15850547/PINK1-DiaPDs)

  • Giuseppe Arena

Deutsche Forschungsgemeinschaft (461705066)

  • Axel Methner

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

Ethics

Human subjects: Induced pluripotent stem cells (iPSCs) from two PD patients carrying the p.Q456X mutation in PINK1 were obtained from the University of Lübeck. Both participants signed a written informed consent according to the Declaration of Helsinki. Ethical approval for conducting iPSC studies in Krüger's lab was granted by the National Committee for Ethics in Research, Luxembourg (Comité National d'Ethique de Recherche; CNER #201411/05).

Copyright

© 2024, Bitar 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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  1. Sara Bitar
  2. Timo Baumann
  3. Christopher Weber
  4. Majd Abusaada
  5. Liliana Rojas-Charry
  6. Patrick Ziegler
  7. Thomas Schettgen
  8. Isabella Eva Randerath
  9. Vivek Venkataramani
  10. Bernhard Michalke
  11. Eva-Maria Hanschmann
  12. Giuseppe Arena
  13. Rejko Krueger
  14. Li Zhang
  15. Axel Methner
(2024)
Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes
eLife 13:e97027.
https://doi.org/10.7554/eLife.97027

Share this article

https://doi.org/10.7554/eLife.97027

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