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Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis

Author

Listed:
  • Clément Bodineau

    (Universidad Pablo de Olavide
    Université de Bordeaux)

  • Mercedes Tomé

    (Universidad Pablo de Olavide)

  • Sarah Courtois

    (Université de Bordeaux)

  • Ana S. H. Costa

    (University of Cambridge
    Cold Spring Harbor Laboratory)

  • Marco Sciacovelli

    (University of Cambridge)

  • Benoit Rousseau

    (University of Bordeaux)

  • Elodie Richard

    (Institut Bergonié)

  • Pierre Vacher

    (Institut Bergonié)

  • Carlos Parejo-Pérez

    (Universidad de Sevilla)

  • Emilie Bessede

    (Université de Bordeaux)

  • Christine Varon

    (Université de Bordeaux)

  • Pierre Soubeyran

    (Institut Bergonié)

  • Christian Frezza

    (University of Cambridge)

  • Piedad del Socorro Murdoch

    (Universidad Pablo de Olavide
    Universidad de Sevilla)

  • Victor H. Villar

    (CRUK Beatson Institute)

  • Raúl V. Durán

    (Universidad Pablo de Olavide
    Université de Bordeaux
    Institut Bergonié)

Abstract

Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.

Suggested Citation

  • Clément Bodineau & Mercedes Tomé & Sarah Courtois & Ana S. H. Costa & Marco Sciacovelli & Benoit Rousseau & Elodie Richard & Pierre Vacher & Carlos Parejo-Pérez & Emilie Bessede & Christine Varon & Pi, 2021. "Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25079-4
    DOI: 10.1038/s41467-021-25079-4
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    Cited by:

    1. Denis Abu Sammour & James L. Cairns & Tobias Boskamp & Christian Marsching & Tobias Kessler & Carina Ramallo Guevara & Verena Panitz & Ahmed Sadik & Jonas Cordes & Stefan Schmidt & Shad A. Mohammed & , 2023. "Spatial probabilistic mapping of metabolite ensembles in mass spectrometry imaging," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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