Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis

  1. Sina C Rosenkranz
  2. Artem A Shaposhnykov
  3. Simone Träger
  4. Jan Broder Engler
  5. Maarten E Witte
  6. Vanessa Roth
  7. Vanessa Vieira
  8. Nanne Paauw
  9. Simone Bauer
  10. Celina Schwencke-Westphal
  11. Charlotte Schubert
  12. Lukas Can Bal
  13. Benjamin Schattling
  14. Ole Pless
  15. Jack van Horssen
  16. Marc Freichel
  17. Manuel A Friese  Is a corresponding author
  1. University Medical Centre Hamburg-Eppendorf, Germany
  2. University Medical Centre Hamburg-Eppendorf Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Germany
  3. Amsterdam UMC, Netherlands
  4. Fraunhofer IME, Germany
  5. University of Heidelberg, Germany

Abstract

While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons resulting in impaired mitochondrial complex IV activity. This was associated with posttranslational inactivation of the transcriptional co-regulator PGC-1α. In mice, neuronal overexpression of Ppargc1a, which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity and maximum respiratory capacity. Moreover, Ppargc1a overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Ppargc1a aggravated neurodegeneration during experimental autoimmune encephalomyelitis (EAE), while neuronal overexpression of Ppargc1a ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.

Data availability

All current data have been provided. Supplemental figures are included in the article file. All individual data are reported within the figure graphs as scatter plots. Numerical data for Figure 3E, 5A and 5C can be found as Source Data.Enrichment analysis was performed using the function 'gseGO' of the R package clusterProfiler; plotting was performed with the R packages ggplot2, clusterProfiler and tidyheatmap.Normalization, calcium spikes, base line detection, and analysis of the calcium clearance rate were performed with the custom-made script written on Python 3.6 (https://github.com/scriptcalcium/PGC1alpha).

The following previously published data sets were used

Article and author information

Author details

  1. Sina C Rosenkranz

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Artem A Shaposhnykov

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Simone Träger

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Jan Broder Engler

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Maarten E Witte

    Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Vanessa Roth

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Vanessa Vieira

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Nanne Paauw

    Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Simone Bauer

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Celina Schwencke-Westphal

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Charlotte Schubert

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Lukas Can Bal

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Benjamin Schattling

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8809-9073
  14. Ole Pless

    ScreeningPort, Fraunhofer IME, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1468-316X
  15. Jack van Horssen

    Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  16. Marc Freichel

    Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1387-2636
  17. Manuel A Friese

    Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
    For correspondence
    manuel.friese@zmnh.uni-hamburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6380-2420

Funding

Stifterverband (Clinician-Scientist Fellowship)

  • Sina C Rosenkranz

Gemeinnützige Hertie-Stiftung (Hertie Network of Excellence in Clinical Neuroscience)

  • Sina C Rosenkranz

Deutsche Forschungsgemeinschaft (FR1720/9-1,FR1720/9-2)

  • Manuel A Friese

Deutsche Forschungsgemeinschaft (FR1638/3-1,FR1638/3-2)

  • Marc Freichel

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

Reviewing Editor

  1. Brandon K Harvey, NIDA/NIH, United States

Ethics

Animal experimentation: All animal care and experimental procedures were performed according to institutional guidelines and conformed to requirements of the German Animal Welfare Act. All animal experiments were approved by the local ethics committee (Behörde für Soziales, Familie, Gesundheit und Verbraucherschutz in Hamburg; G22/13 and 122/17). We conducted all procedures in accordance with the ARRIVE guidelines (Kilkenny et al., 2010).

Version history

  1. Received: August 5, 2020
  2. Accepted: February 10, 2021
  3. Accepted Manuscript published: February 10, 2021 (version 1)
  4. Version of Record published: March 25, 2021 (version 2)
  5. Version of Record updated: February 2, 2022 (version 3)

Copyright

© 2021, Rosenkranz 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. Sina C Rosenkranz
  2. Artem A Shaposhnykov
  3. Simone Träger
  4. Jan Broder Engler
  5. Maarten E Witte
  6. Vanessa Roth
  7. Vanessa Vieira
  8. Nanne Paauw
  9. Simone Bauer
  10. Celina Schwencke-Westphal
  11. Charlotte Schubert
  12. Lukas Can Bal
  13. Benjamin Schattling
  14. Ole Pless
  15. Jack van Horssen
  16. Marc Freichel
  17. Manuel A Friese
(2021)
Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis
eLife 10:e61798.
https://doi.org/10.7554/eLife.61798

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https://doi.org/10.7554/eLife.61798

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