Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
Patrick Metang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
Nathan Egge
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
Yingjian Liu
Department of Mechanical Engineering, University of Texas at Dallas, Dallas, United States
Kielen R Zuurbier
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; O’Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, United States
Karthigayini Sivaprakasam
O’Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, United States; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
Shawn Shirazi
Department of Integrative Biology, University of California, Berkeley, Berkeley, United States
Ashleigh Chuah
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
O’Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, United States; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
Dong Qian
Department of Mechanical Engineering, University of Texas at Dallas, Dallas, United States
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
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.
