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Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo

  1. King Faisal Yambire
  2. Christine Rostosky
  3. Takashi Watanabe
  4. David Pacheu-Grau
  5. Sylvia Torres-Odio
  6. Angela Sanchez-Guerrero
  7. Ola Senderovich
  8. Esther G Meyron-Holtz
  9. Ira Milosevic
  10. Jens Frahm
  11. A Phillip West
  12. Nuno Raimundo  Is a corresponding author
  1. University Medical Center Göttingen, Germany
  2. European Neuroscience Institute, Germany
  3. Max-Planck Institute for Biophysical Chemistry, Germany
  4. Texas A&M University Health Science Center, United States
  5. Technion Israel Institute of Technology, Israel
Research Article
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Cite this article as: eLife 2019;8:e51031 doi: 10.7554/eLife.51031

Abstract

Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo.

Article and author information

Author details

  1. King Faisal Yambire

    Institute of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Christine Rostosky

    Synaptic Vesicle Recycling, European Neuroscience Institute, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Takashi Watanabe

    Biomedizinische NMR, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. David Pacheu-Grau

    Institute of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Sylvia Torres-Odio

    Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Angela Sanchez-Guerrero

    Institute of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Ola Senderovich

    Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Esther G Meyron-Holtz

    Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Ira Milosevic

    Synaptic Vesicle Recycling, European Neuroscience Institute, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6440-3763
  10. Jens Frahm

    Biomedizinische NMR, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8279-884X
  11. A Phillip West

    Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nuno Raimundo

    Institute of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
    For correspondence
    nuno.raimundo@med.uni-goettingen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5988-9129

Funding

H2020 European Research Council (337327)

  • Nuno Raimundo

Deutsche Forschungsgemeinschaft (SFB1190-P02)

  • Ira Milosevic
  • Nuno Raimundo

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

Ethics

Animal experimentation: The experiments were performed under the permit 15-883 by the authority for animal research in Lower Saxony, Germany (LAVES).

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Publication history

  1. Received: August 12, 2019
  2. Accepted: December 2, 2019
  3. Accepted Manuscript published: December 3, 2019 (version 1)

Copyright

© 2019, Yambire 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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