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

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, Pierre Soubeyran, Christian Frezza, Piedad del Socorro Murdoch, Victor H. Villar and Raúl V. Durán ()
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Clément Bodineau: Universidad Pablo de Olavide
Mercedes Tomé: Universidad Pablo de Olavide
Sarah Courtois: Université de Bordeaux
Ana S. H. Costa: University of Cambridge
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
Victor H. Villar: CRUK Beatson Institute
Raúl V. Durán: Universidad Pablo de Olavide

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

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25079-4

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DOI: 10.1038/s41467-021-25079-4

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