Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

• DOI: 10.7554/elife.69438
• Publication Date: 2021-09-02T16:00:41Z
• Authors: Rene Solano Fonseca; Patrick Metang; Nathan Egge; Yingjian Liu; Kielen R Zuurbier; Karthigayini Siva...; Shawn Shirazi; Ashleigh Chuah; Sonja LB Arneaud; Genevieve Konopka; Dong Qian; Peter M Douglas
• Keywords: QH301-705.5; Science; Mice; 03 medical and health sciences; Brain Injuries, Traumatic; Animals; Humans; Biology (General); Caenorhabditis elegans; Cells, Cultured; 0303 health sciences; traumatic brain injury; Dopaminergic Neurons; Q; neurodegeneration; astrocytes; R; Cell Biology; Neuroprotection; 3. Good health; mitochondria; HEK293 Cells; Astrocytes; Nerve Degeneration; Medicine; metabolism; Glycolysis

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.