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; Raúl V. Durán

doi:10.1038/s41467-021-25079-4

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, Raúl V. Durán^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	4814
Number of pages	13
Journal	Nature Communications
Volume	12
DOIs	https://doi.org/10.1038/s41467-021-25079-4
Publication status	Published - 10 Aug 2021

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Bodineau, C., Tomé, M., Courtois, S., Costa, A. S. H., Sciacovelli, M., Rousseau, B., Richard, E., Vacher, P., Parejo-Pérez, C., Bessede, E., Varon, C., Soubeyran, P., Frezza, C., Murdoch, P. D. S., Villar, V. H., & Durán, R. V. (2021). Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis. Nature Communications, 12, Article 4814. https://doi.org/10.1038/s41467-021-25079-4

@article{b36335eb4cd74764babfca2f664f1e87,

title = "Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis",

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.",

author = "Cl{\'e}ment Bodineau and Mercedes Tom{\'e} and Sarah Courtois and Costa, {Ana S.H.} and Marco Sciacovelli and Benoit Rousseau and Elodie Richard and Pierre Vacher and Carlos Parejo-P{\'e}rez and Emilie Bessede and Christine Varon and Pierre Soubeyran and Christian Frezza and Murdoch, {Piedad del Socorro} and Villar, {Victor H.} and Dur{\'a}n, {Ra{\'u}l V.}",

note = "Funding: This work was supported by funds from the following institutions: Agencia Estatal de Investigaci{\'o}n/European Regional Development Fund, European Union (PGC2018-096244-B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale —INSERM, Universit{\'e} de Bordeaux, Fondation pour la Recherche M{\'e}dicale, the Conseil R{\'e}gional d{\textquoteright}Aquitaine, SIRIC-BRIO, Fondation ARC, and Institut Europ{\'e}en de Chimie et Biologie. C.B. was recipient of fellowships from the Minister of Higher Education, Research and Innovation (France) and the Fondation ARC (France).",

year = "2021",

month = aug,

day = "10",

doi = "10.1038/s41467-021-25079-4",

language = "English",

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Bodineau, C, Tomé, M, Courtois, S, Costa, ASH, Sciacovelli, M, Rousseau, B, Richard, E, Vacher, P, Parejo-Pérez, C, Bessede, E, Varon, C, Soubeyran, P, Frezza, C, Murdoch, PDS, Villar, VH & Durán, RV 2021, 'Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis', Nature Communications, vol. 12, 4814. https://doi.org/10.1038/s41467-021-25079-4

TY - JOUR

T1 - Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis

AU - Bodineau, Clément

AU - Tomé, Mercedes

AU - Courtois, Sarah

AU - Costa, Ana S.H.

AU - Sciacovelli, Marco

AU - Rousseau, Benoit

AU - Richard, Elodie

AU - Vacher, Pierre

AU - Parejo-Pérez, Carlos

AU - Bessede, Emilie

AU - Varon, Christine

AU - Soubeyran, Pierre

AU - Frezza, Christian

AU - Murdoch, Piedad del Socorro

AU - Villar, Victor H.

AU - Durán, Raúl V.

N1 - Funding: This work was supported by funds from the following institutions: Agencia Estatal de Investigación/European Regional Development Fund, European Union (PGC2018-096244-B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Santé et de la Recherche Médicale —INSERM, Université de Bordeaux, Fondation pour la Recherche Médicale, the Conseil Régional d’Aquitaine, SIRIC-BRIO, Fondation ARC, and Institut Européen de Chimie et Biologie. C.B. was recipient of fellowships from the Minister of Higher Education, Research and Innovation (France) and the Fondation ARC (France).

PY - 2021/8/10

Y1 - 2021/8/10

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-021-25079-4

DO - 10.1038/s41467-021-25079-4

M3 - Article

C2 - 34376668

AN - SCOPUS:85112103090

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

M1 - 4814

ER -

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

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