Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

Rene Solano Fonseca, Patrick Metang, Nathan Egge, Yingjian Liu, Kielen R. Zuurbier, Karthigayini Sivaprakasam, Shawn Shirazi, Ashleigh Chuah, Sonja L.B. Arneaud, Genevieve Konopka, Dong Qian, Peter M. Douglas

Research output: Contribution to journalArticlepeer-review

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, PDHE1a. 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.

Original languageEnglish (US)
Article numbere69438
JournaleLife
Volume10
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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