@article{15ef7f96ac264a6f9b9c8485e1288f4a,
title = "Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration",
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, PDHE1a. 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.",
author = "Fonseca, {Rene Solano} and Patrick Metang and Nathan Egge and Yingjian Liu and Zuurbier, {Kielen R.} and Karthigayini Sivaprakasam and Shawn Shirazi and Ashleigh Chuah and Arneaud, {Sonja L.B.} and Genevieve Konopka and Dong Qian and Douglas, {Peter M.}",
note = "Funding Information: We thank Massimo Zeviani, PhD at the University of Padua for providing Surf1 mutant mice. We thank Lauren Zacharias, MS and Ralph DeBerardinis, MD, PhD of the Children{\textquoteright}s Medical Center Metabolomics Facility at UT Southwestern Medical Center (UTSW) for targeted metabolomic profiling and advice on data analysis. We thank Syann Lee, PhD at the Metabolic Phenotyping Core at UTSW for overseeing mouse metabolic cage experiments. We thank Matt Seiber, PhD, William Dauer, MD, Munro Cullum, PhD at UTSW, and Michael Douglas, PhD for critical feedback. Funding: Our funding sources are from the Clayton Foundation for Research, Welch foundation (I-2061– 20210327 to PMD), the American Federation of Aging Research, the Glenn Center for Aging, the NIH (R00AG042495 and R01AG061338 to PMD), and the Cancer Prevention Research Institute of Texas (CPRIT) (RR150089 to PMD). Funding Information: Our funding sources are from the Clayton Foundation for Research, Welch foundation (I-2061? 20210327 to PMD), the American Federation of Aging Research, the Glenn Center for Aging, the NIH (R00AG042495 and R01AG061338 to PMD), and the Cancer Prevention Research Institute of Texas (CPRIT) (RR150089 to PMD).Funder Grant reference number Author Welch Foundation I-2061-20210327 Peter M Douglas National Institutes of Health R01AG061338 Peter M Douglas Cancer Prevention and Research Institute of Texas Clayton Foundation for Research RR150089 Peter M Douglas Peter M Douglas National Institutes of Health R00AG042495 Peter M Douglas. Publisher Copyright: {\textcopyright} Solano Fonseca et al.",
year = "2021",
month = sep,
doi = "10.7554/eLife.69438",
language = "English (US)",
volume = "10",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}