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
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.
