1. Immunology and Inflammation
  2. Neuroscience
Download icon

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
Research Article
  • Cited 0
  • Views 626
  • Annotations
Cite this article as: eLife 2021;10:e61798 doi: 10.7554/eLife.61798

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.

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.

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).

Reviewing Editor

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

Publication history

  1. Received: August 5, 2020
  2. Accepted: February 10, 2021
  3. Accepted Manuscript published: February 10, 2021 (version 1)

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.

Metrics

  • 626
    Page views
  • 162
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Kathryn Milne et al.
    Research Article

    Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease rapidly expand in naive hosts, we found no transcriptional evidence to support this hypothesis. These data indicate that parasite variants that dominate severe malaria do not have an intrinsic growth or survival advantage; instead, they presumably rely upon infection-induced changes in their within-host environment for selection.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Yasmine Issah et al.
    Research Article

    Adverse early-life exposures have a lasting negative impact on health. Neonatal hyperoxia that is a risk factor for bronchopulmonary dysplasia confers susceptibility to influenza A virus (IAV) infection later in life. Given our previous findings that the circadian clock protects against IAV, we asked if the long-term impact of neonatal hyperoxia vis-à-vis IAV infection includes circadian disruption. Here, we show that neonatal hyperoxia abolishes the clock-mediated time of day protection from IAV in mice, independent of viral burden through host tolerance pathways. We discovered that the lung intrinsic clock (and not the central or immune clocks) mediated this dysregulation. Loss of circadian protein, Bmal1, in alveolar type 2 (AT2) cells recapitulates the increased mortality, loss of temporal gating, and other key features of hyperoxia-exposed animals. Our data suggest a novel role for the circadian clock in AT2 cells in mediating long-term effects of early-life exposures to the lungs.