Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

eLife

Shawn Shirazi¹  Dong Qian²  Yingjian Liu²  Rene Solano Fonseca³  Ashleigh Chuah³  Sonja LB Arneaud³  Nathan Egge³  Patrick Metang³  Peter M Douglas⁴  Kielen R Zuurbier⁵  Genevieve Konopka⁶  Karthigayini Sivaprakasam⁶ 

[1] Department of Integrative Biology, University of California, Berkeley, Berkeley, United States;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;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;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;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;

关键词: traumatic brain injury;    neurodegeneration;    mitochondria;    astrocytes;    metabolism;    C. elegans;    Mouse;   

DOI  :  10.7554/eLife.69438

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY