Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

  1. Rene Solano Fonseca
  2. Patrick Metang
  3. Nathan Egge
  4. Yingjian Liu
  5. Kielen R Zuurbier
  6. Karthigayini Sivaprakasam
  7. Shawn Shirazi
  8. Ashleigh Chuah
  9. Sonja LB Arneaud
  10. Genevieve Konopka
  11. Dong Qian
  12. Peter M Douglas  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. University of Texas at Dallas, United States
  3. University of California Berkeley, United States

Abstract

Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

Data availability

All datasets are submitted to GEO and will be made available to the public upon publication of the article.

The following data sets were generated

Article and author information

Author details

  1. Rene Solano Fonseca

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  2. Patrick Metang

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. Nathan Egge

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. Yingjian Liu

    Department of Mechanical Engineering, University of Texas at Dallas, Dallas, United States
    Competing interests
    No competing interests declared.
  5. Kielen R Zuurbier

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Karthigayini Sivaprakasam

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  7. Shawn Shirazi

    Department of Integrative Biology, University of California Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  8. Ashleigh Chuah

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  9. Sonja LB Arneaud

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1123-3876
  10. Genevieve Konopka

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Genevieve Konopka, Reviewing Editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3363-7302
  11. Dong Qian

    Department of Mechanical Engineering, University of Texas at Dallas, Dallas, United States
    Competing interests
    No competing interests declared.
  12. Peter M Douglas

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    peter.douglas@utsouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0734-1049

Funding

Welch Foundation (I-2061-20210327)

  • Peter M Douglas

National Institutes of Health (R01AG061338)

  • Peter M Douglas

Cancer Prevention and Research Institute of Texas (RR150089)

  • Peter M Douglas

Clayton Foundation for Research

  • Peter M Douglas

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

Reviewing Editor

  1. Scott F Leiser, University of Michigan, United States

Ethics

Animal experimentation: All mouse studies were approved by the UT Southwestern Medical Center Institutional Animal Care and Use Committee (IACUC) protocols (#2016-101750) and performed in accordance with institutional and federal guidelines.

Version history

  1. Received: April 15, 2021
  2. Accepted: August 24, 2021
  3. Accepted Manuscript published: September 2, 2021 (version 1)
  4. Version of Record published: September 17, 2021 (version 2)

Copyright

© 2021, Solano Fonseca 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. Rene Solano Fonseca
  2. Patrick Metang
  3. Nathan Egge
  4. Yingjian Liu
  5. Kielen R Zuurbier
  6. Karthigayini Sivaprakasam
  7. Shawn Shirazi
  8. Ashleigh Chuah
  9. Sonja LB Arneaud
  10. Genevieve Konopka
  11. Dong Qian
  12. Peter M Douglas
(2021)
Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration
eLife 10:e69438.
https://doi.org/10.7554/eLife.69438

Share this article

https://doi.org/10.7554/eLife.69438

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