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

Author

Listed:
  • 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
    LMU Munich)

  • Thomas Carell

    (Ludwig-Maximilians-Universität München)

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.

Suggested Citation

  • 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 & M, 2021. "Redirected nuclear glutamate dehydrogenase supplies Tet3 with α-ketoglutarate in neurons," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24353-9
    DOI: 10.1038/s41467-021-24353-9
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    Cited by:

    1. Valdemaras Petrosius & Pedro Aragon-Fernandez & Nil Üresin & Gergo Kovacs & Teeradon Phlairaharn & Benjamin Furtwängler & Jeff Op De Beeck & Sarah L. Skovbakke & Steffen Goletz & Simon Francis Thomsen, 2023. "Exploration of cell state heterogeneity using single-cell proteomics through sensitivity-tailored data-independent acquisition," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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