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

doi:10.1016/j.celrep.2023.112335

Neurons require glucose uptake and glycolysis in vivo

Cell Rep. 2023 Apr 25;42(4):112335. doi: 10.1016/j.celrep.2023.112335. Epub 2023 Apr 6.

Authors

Huihui Li¹, Caroline Guglielmetti², Yoshitaka J Sei¹, Misha Zilberter¹, Lydia M Le Page², Lauren Shields³, Joyce Yang⁴, Kevin Nguyen¹, Brice Tiret², Xiao Gao⁵, Neal Bennett¹, Iris Lo¹, Talya L Dayton⁶, Martin Kampmann⁷, Yadong Huang⁸, Jeffrey C Rathmell⁹, Matthew Vander Heiden¹⁰, Myriam M Chaumeil¹¹, Ken Nakamura¹²

Affiliations

¹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
² Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA.
³ 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.
⁴ Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA.
⁵ 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.
⁶ Koch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ 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.
⁸ 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.
⁹ Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁰ 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.
¹¹ 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. Electronic address: myriam.chaumeil@ucsf.edu.
¹² 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. Electronic address: ken.nakamura@gladstone.ucsf.edu.

Abstract

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.

Keywords: CP: Neuroscience; bioenergetics; brain energy; galactose metabolism; glucose transporter; glycolysis; hyperpolarized magnetic resonance spectroscopic imaging; metabolomics; neuronal glucose metabolism; pyruvate kinase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Energy Metabolism*
Female
Glucose / metabolism
Glycolysis* / physiology
Humans
Magnetic Resonance Imaging
Mice
Neurons / metabolism

Substances

Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding