Glutamine influx licenses macrophage glutaminolysis for restorative functions in atherosclerosis
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ABSTRACT:
PROVIDER: PRJNA1292015 | ENA |
REPOSITORIES: ENA
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Project description:Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates whether they ameliorate or exacerbate pathogenesis. Here, we found that glutamine synthetase served as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relied more heavily on glutamine influx and glutaminase activity. Cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodeling and restorative functions. Thus, we uncover a role of glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.
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Project description:Oxidative phosphorylation (OXPHOS) fulfills energy metabolism and biosynthesis through tricarboxylic acid (TCA) cycle and an intact electron transport chain (ETC). Mitochondrial glutamine import (MGI) replenishes TCA cycle through glutaminolysis, but its broader roles in cancer remains unclear. Here we show that MGI sustains OXPHOS independent of glutaminolysis, by maintaining ETC integrity. Exogenous glutamate availability abrogates cellular dependence on glutaminolysis but not SLC1A5var-mediated MGI. Blocking MGI elicits severe mitochondrial defects, reducing mitochondrial glucose oxidation and increasing glutamine reductive carboxylation. MGI but not glutaminolysis is essential for mitochondrial translation by enabling biogenesis of Gln-mt-tRNAGln, the most limiting mitochondrial aminoacyl-tRNA in cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in human tumors inhibit Gln-mt-tRNAGln biogenesis, mitochondrial translation and blunt tumor growth. Our findings uncover a previously unrecognized role of MGI in safeguarding mitochondrial translation independent of glutaminolysis, and inform a therapeutic option by targeting MGI to abrogate OXPHOS for cancer treatment.
2025-09-30 | PXD069373 |
Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is a hallmark of atherosclerotic diseases. We used single nuclei RNA sequencing (snRNA-seq) to analyze the impact of defective hepatic glutaminolysis on cell diversity in atherosclerotic aorta.
2024-10-17 | GSE269682 | GEO
Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common in atherosclerotic cardiovascular disease. Here, we reveal that modulation of glutaminolysis or glutamate availability in culture media is critical for smooth muscle cell line (MOVAS) phenotypic switching. Cells were treated for 24 hours with glutaminase inhibitors (50mM DON, Sigma-SML0601) in presence or absence of 2mM glutamate suplementation (Gibco-35050061). High-throughput transcriptional profiling revealed that modulation of glutamine and glutamate homeostasis impacted genes involved in protein and extracellular matrix organization, cell motility and microtubule. Thus, we uncovered a novel role for glutamine metabolism in the phenotypic switch in SMCs, a hallmark of vascular remodelling.
2024-10-17 | GSE270058 | GEO
Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common in atherosclerotic cardiovascular disease. Here, we reveal that modulation of glutaminolysis or glutamate availability in culture media is critical for smooth muscle cell line (MOVAS) phenotypic switching. Cells were treated for 24 hours with glutaminase inhibitors (50mM DON, Sigma-SML0601) in presence or absence of 2mM glutamate suplementation (Gibco-35050061). High-throughput transcriptional profiling revealed that modulation of glutamine and glutamate homeostasis impacted genes involved in protein and extracellular matrix organization, cell motility and microtubule. Thus, we uncovered a novel role for glutamine metabolism in the phenotypic switch in SMCs, a hallmark of vascular remodelling.
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Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.
2016-11-14 | GSE65083 | GEO
Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.
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Project description:The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.
| S-EPMC11612431 | biostudies-literature
Project description:External mechanical stimuli are pivotal for the maintenance of bone homeostasis via enhancing bone formation and inhibiting bone resorption. Lack of mechanical loading during prolonged bed rest or exposure to long-term microgravity environment in space leads to a rapid decline in bone mass and bone strength. Osteoblast lineage cells are capable of sensing and transmitting mechanical signals through a variety of pathways. However, the mechanisms by which osteoclasts perceive and respond to mechanical disturbances remain largely unclear. Here, through integrating the data of single-cell transcriptome, metabolome, proteome and ubiquitinome of bone tissues from hindlimb unloading (HLU) and control mice, we clarify that in the absence of mechanical force, osteoclasts are characterized by significant increase in Gln influx and catabolism, as well as suppression of intrinsic apoptosis.
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Project description:Cancer cells heavily depend on the amino acid, glutamine, to meet the demands associated with growth and proliferation. Due to its rapid consumption, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation using RNA-seq analysis. We show that Slc7a3, an arginine transporter, is significantly induced by p53. We show the concomitant rise in intracellular arginine levels following glutamine deprivation is dependent on p53. The influx of arginine has minimal effect on known metabolic pathways upon glutamine deprivation. Instead, we found arginine serves as an effector for mTORC1 activation to promote in vitro and in vivo cell growth in response to glutamine starvation. Therefore, we identify a novel p53-inducible gene that contributes to the metabolic stress response.
2019-05-15 | GSE125782 | GEO