Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration
- University of Texas Southwestern Medical Center, United States
- University of Texas at Dallas, United States
- 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.
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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.
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.
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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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration
eLife 10:e69438.
https://doi.org/10.7554/eLife.69438
