Redirected nuclear glutamate dehydrogenase supplies Tet3 with α-ketoglutarate in neurons

Franziska R. Traube, Dilara Özdemir, Hanife Sahin, Constanze Scheel, Andrea F. Glück, Anna S. Geserich, Sabine Oganesian, Sarantos Kostidis, Katharina Iwan, René Rahimoff, Grazia Giorgio, Markus Müller, Fabio Spada, Martin Biel, Jürgen Cox, Martin Giera, Stylianos Michalakis () and Thomas Carell ()
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Franziska R. Traube: Ludwig-Maximilians-Universität München
Dilara Özdemir: Ludwig-Maximilians-Universität München
Hanife Sahin: Ludwig-Maximilians-Universität München
Constanze Scheel: Ludwig-Maximilians-Universität München
Andrea F. Glück: Ludwig-Maximilians-Universität München
Anna S. Geserich: Ludwig-Maximilians-Universität München
Sabine Oganesian: Ludwig-Maximilians-Universität München
Sarantos Kostidis: Leiden University Medical Center, Center for Proteomics and Metabolomics
Katharina Iwan: Ludwig-Maximilians-Universität München
René Rahimoff: Ludwig-Maximilians-Universität München
Grazia Giorgio: Ludwig-Maximilians-Universität München
Markus Müller: Ludwig-Maximilians-Universität München
Fabio Spada: Ludwig-Maximilians-Universität München
Martin Biel: Ludwig-Maximilians-Universität München
Jürgen Cox: Computational Systems Biochemistry, Max Planck Institute of Biochemistry
Martin Giera: Leiden University Medical Center, Center for Proteomics and Metabolomics
Stylianos Michalakis: Ludwig-Maximilians-Universität München
Thomas Carell: Ludwig-Maximilians-Universität München

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Tet3 is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How αKG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an unresolved question in the connection between metabolism and epigenetics. We show that in neurons the mitochondrial enzyme glutamate dehydrogenase, which converts glutamate into αKG in an NAD+-dependent manner, is redirected to the nucleus by the αKG-consumer protein Tet3, suggesting on-site production of αKG. Further, glutamate dehydrogenase has a stimulatory effect on Tet3 demethylation activity in neurons, and neuronal activation increases the levels of αKG. Overall, the glutamate dehydrogenase-Tet3 interaction might have a role in epigenetic changes during neural plasticity.

Date: 2021
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DOI: 10.1038/s41467-021-24353-9

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