Neurons require glucose uptake and glycolysis in vivo

Huihui Li; Caroline Guglielmetti; Yoshitaka J. Sei; Misha Zilberter; Lydia M. Le Page; Lauren Shields; Joyce Yang; Kevin Nguyen; Brice Tiret; Xiao Gao; Neal Bennett; Iris Lo; Talya L. Dayton; Martin Kampmann; Yadong Huang; Jeffrey C. Rathmell; Matthew Vander Heiden; Myriam M. Chaumeil; Ken Nakamura

Cell Reports (Apr 2023)

Neurons require glucose uptake and glycolysis in vivo

Huihui Li,
Caroline Guglielmetti,
Yoshitaka J. Sei,
Misha Zilberter,
Lydia M. Le Page,
Lauren Shields,
Joyce Yang,
Kevin Nguyen,
Brice Tiret,
Xiao Gao,
Neal Bennett,
Iris Lo,
Talya L. Dayton,
Martin Kampmann,
Yadong Huang,
Jeffrey C. Rathmell,
Matthew Vander Heiden,
Myriam M. Chaumeil,
Ken Nakamura

Affiliations

Huihui Li: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
Caroline Guglielmetti: Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA
Yoshitaka J. Sei: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
Misha Zilberter: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
Lydia M. Le Page: Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA
Lauren Shields: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Joyce Yang: Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA
Kevin Nguyen: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
Brice Tiret: Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA
Xiao Gao: Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA; UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA 94158, USA
Neal Bennett: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
Iris Lo: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
Talya L. Dayton: Koch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Martin Kampmann: Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA; UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
Yadong Huang: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Jeffrey C. Rathmell: Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Matthew Vander Heiden: Koch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA
Myriam M. Chaumeil: Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding author
Ken Nakamura: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 4
p. 112335

Abstract

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Summary: Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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