TY - JOUR TI - Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration AU - Solano Fonseca, Rene AU - Metang, Patrick AU - Egge, Nathan AU - Liu, Yingjian AU - Zuurbier, Kielen R AU - Sivaprakasam, Karthigayini AU - Shirazi, Shawn AU - Chuah, Ashleigh AU - Arneaud, Sonja LB AU - Konopka, Genevieve AU - Qian, Dong AU - Douglas, Peter M A2 - Leiser, Scott F A2 - Kaeberlein, Matt VL - 10 PY - 2021 DA - 2021/09/02 SP - e69438 C1 - eLife 2021;10:e69438 DO - 10.7554/eLife.69438 UR - https://doi.org/10.7554/eLife.69438 AB - 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. KW - traumatic brain injury KW - neurodegeneration KW - mitochondria KW - astrocytes KW - metabolism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -