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.
Highlights
Selective vulnerability of different neuronal subtypes to dysfunction, degeneration, and death underlies all neurological diseases
Utilizing our C. elegans trauma model, we found that reducing the complex IV cytochrome C oxidase activity of the electron transport chain (ETC) through cox-5b RNAi promotes a dose-dependent survival of dopaminergic neurons after injury (Figure 3A and B)
We describe a comparative animal model to identify conserved molecular mechanisms operating in traumatic brain injury (TBI)
Summary
Selective vulnerability of different neuronal subtypes to dysfunction, degeneration, and death underlies all neurological diseases. Differential interplay between genetic and environmental factors contribute to this neuronal selectivity. Environmental stimuli have the capacity to trigger pathogenic cascades contingent on genetic factors. Such is the case for traumatic brain injury (TBI) and concussion, in which the initial biomechanical insult precipitates numerous cellular and systemic alterations with the potential to promote neurological dysfunction and progressive neurodegeneration. Ionic imbalances, cytoskeletal disruption, aberrant proteostasis, genomic instability, and mitochondrial dysfunction within neurons and support cells initiate systemic abnormalities including metabolic impairment, vascular disruption, inflammation, blood-brain barrier defects, and reduced cerebral blood-flow (Giza et al, 2018).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
