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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

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.

SUBMITTER: Solano Fonseca R

PROVIDER: S-EPMC8448530 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

Solano Fonseca Rene R Metang Patrick P Egge Nathan N Liu Yingjian Y Zuurbier Kielen R KR Sivaprakasam Karthigayini K Shirazi Shawn S Chuah Ashleigh A Arneaud Sonja Lb SL Konopka Genevieve G Qian Dong D Douglas Peter M PM

eLife 20210902

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 <i>C. elegans</i> to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced d ...[more]

PMID: 34473622

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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

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