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.
2025-09-01 | GSE302738 | GEO
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:<p>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.</p>
2025-09-29 | MTBLS13076 | MetaboLights
Project description:<p>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.</p>
2025-09-29 | MTBLS13074 | MetaboLights
Project description:<p>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.</p>
2025-09-29 | MTBLS13075 | MetaboLights
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 | GSE270056 | 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: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.
2016-11-14 | GSE63380 | GEO