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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.

SUBMITTER: Bodineau C

PROVIDER: S-EPMC8355106 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Bodineau Clément C Tomé Mercedes M Courtois Sarah S Costa Ana S H ASH Sciacovelli Marco M Rousseau Benoit B Richard Elodie E Vacher Pierre P Parejo-Pérez Carlos C Bessede Emilie E Varon Christine C Soubeyran Pierre P Frezza Christian C Murdoch Piedad Del Socorro PDS Villar Victor H VH Durán Raúl V RV

Nature communications 20210810 1

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 AT ...[more]

PMID: 34376668

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Project description:Energy metabolism in proliferating cultured rat thymocytes was compared with that of freshly prepared non-proliferating resting cells. Cultured rat thymocytes enter a proliferative cycle after stimulation by concanavalin A and Lymphocult T (interleukin-2), with maximal rates of DNA synthesis at 60 h. Compared with incubated resting thymocytes, glucose metabolism by incubated proliferating thymocytes was 53-fold increased; 90% of the amount of glucose utilized was converted into lactate, whereas resting cells metabolized only 56% to lactate. However, the latter oxidized 27% of glucose to CO2, as opposed to 1.1% by the proliferating cells. Activities of hexokinase, 6-phosphofructokinase, pyruvate kinase and aldolase in proliferating thymocytes were increased 12-, 17-, 30- and 24-fold respectively, whereas the rate of pyruvate oxidation was enhanced only 3-fold. The relatively low capacity of pyruvate degradation in proliferating thymocytes might be the reason for almost complete conversion of glucose into lactate by these cells. Glutamine utilization by rat thymocytes was 8-fold increased during proliferation. The major end products of glutamine metabolism are glutamate, aspartate, CO2 and ammonia. A complete recovery of glutamine carbon and nitrogen in the products was obtained. The amount of glutamate formed by phosphate-dependent glutaminase which entered the citric acid cycle was enhanced 5-fold in the proliferating cells: 76% was converted into 2-oxoglutarate by aspartate aminotransferase, present in high activity, and the remaining 24% by glutamate dehydrogenase. With resting cells the same percentages were obtained (75 and 25). Maximal activities of glutaminase, glutamate dehydrogenase and aspartate aminotransferase were increased 3-, 12- and 6-fold respectively in proliferating cells; 32% of the glutamate metabolized in the citric acid cycle was recovered in CO2 and 61% in aspartate. In resting cells this proportion was 41% and 59% and in mitogen-stimulated cells 39% and 65% respectively. Addition of glucose (4 mM) or malate (2 mM) strongly decreased the rates of glutamine utilization and glutamate conversion into 2-oxoglutarate by proliferating thymocytes and also affected the pathways of further glutamate metabolism. Addition of 2 mM-pyruvate did not alter the rate of glutamine utilization by proliferating thymocytes, but decreased the rate of metabolism beyond the stage of glutamate significantly. Formation of acetyl-CoA in the presence of pyruvate might explain the relatively enhanced oxidation of glutamate to CO2 (56%) by proliferating thymocytes.

Project description:Paenibacillus polymyxa WLY78, a N2-fixing bacterium, has great potential use as a biofertilizer in agriculture. Recently, we have revealed that GlnR positively and negatively regulates the transcription of the nif (nitrogen fixation) operon (nifBHDKENXhesAnifV) in P. polymyxa WLY78 by binding to two loci of the nif promoter according to nitrogen availability. However, the regulatory mechanisms of nitrogen metabolism mediated by GlnR in the Paenibacillus genus remain unclear. In this study, we have revealed that glutamine synthetase (GS) and GlnR in P. polymyxa WLY78 play a key role in the regulation of nitrogen metabolism. P. polymyxa GS (encoded by glnA within glnRA) and GS1 (encoded by glnA1) belong to distinct groups: GSI-α and GSI-β. Both GS and GS1 have the enzyme activity to convert NH4+ and glutamate into glutamine, but only GS is involved in the repression by GlnR. GlnR represses transcription of glnRA under excess nitrogen, while it activates the expression of glnA1 under nitrogen limitation. GlnR simultaneously activates and represses the expression of amtBglnK and gcvH in response to nitrogen availability. Also, GlnR regulates the expression of nasA, nasD1D2, nasT, glnQHMP, and glnS. IMPORTANCE In this study, we have revealed that Paenibacillus polymyxa GlnR uses multiple mechanisms to regulate nitrogen metabolism. GlnR activates or represses or simultaneously activates and inhibits the transcription of nitrogen metabolism genes in response to nitrogen availability. The multiple regulation mechanisms employed by P. polymyxa GlnR are very different from Bacillus subtilis GlnR which represses nitrogen metabolism under excess nitrogen. Both GS encoded by glnA within the glnRA operon and GS1 encoded by glnA1 in P. polymyxa WLY78 are involved in ammonium assimilation, but only GS is required for regulating GlnR activity. The work not only provides significant insight into understanding the interplay of GlnR and GS in nitrogen metabolism but also provides guidance for improving nitrogen fixation efficiency by modulating nitrogen metabolism.

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

Publications

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

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