The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade
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ABSTRACT:
PROVIDER: PRJNA1098755 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28618070_1.fastq.gz | Fastqsanger.gz | |||
| SRR28618070_2.fastq.gz | Fastqsanger.gz | |||
| SRR28618071_1.fastq.gz | Fastqsanger.gz | |||
| SRR28618071_2.fastq.gz | Fastqsanger.gz | |||
| SRR28618072_1.fastq.gz | Fastqsanger.gz |
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Project description:Angiogenesis, the formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings such as cancer and ischemia. Given its critical role, the regulation of endothelial growth factor receptor (e.g. VEGFR2, FGFR1) represents important mechanisms for the control of angiogenesis. Recent evidences support cell metabolism as a critical regulator of angiogenesis. However, it is unknown how glutamine metabolism regulates growth factor receptor expression. Here, by using genetic and pharmacological approaches, we show that glutaminolysis and glutamate-dependent transaminases (TAs) support alpha-ketoglutarate (αKG) levels and are critical regulators of angiogenic response during pathological conditions. Indeed, the endothelial specific blockage of GLS1 impairs ischemic and tumor angiogenesis by suppressing VEGFR2 translation via mTORC1-dependent pathway. Lastly, we discover that ECs catabolized the glutamine-derived glutamate via phosphoserine aminotransferase 1 (PSAT1) as crucial to support VEGFR2 translation. These findings identify glutamine anaplerosis and TA activity as a critical regulator of growth factor receptor translation in normal and pathological angiogenesis. We anticipate our studies to be a starting point for novel anti-angiogenesis approaches based on GLS1/PSAT1 inhibitor treatments to overcome anti-VEGF therapies resistance.
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Project description:By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that, branching off from glycolysis, the serine biosynthesis pathway (SBP) is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSCs activation and expansion of myogenic progenitors through production of the metabolite -ketoglutarate (-KG) and the -KG-generated amino acid glutamine. Genetic ablation of Psat1 in MuSCs resulted in defective expansion of MuSCs and impaired regeneration. Psat1, -KG, and glutamine were reduced in MuSCs of old mice and myoblasts of old individuals. -KG or glutamine re-established appropriate muscle regeneration of adult Psat1-/- mice, old mice, and improved proliferation of old human myoblasts. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest -KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.
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Project description:By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that, branching off from glycolysis, the serine biosynthesis pathway (SBP) is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSCs activation and expansion of myogenic progenitors through production of the metabolite a-ketoglutarate (a-KG) and the a-KG-generated amino acid glutamine. Genetic ablation of Psat1 in MuSCs resulted in defective expansion of MuSCs and impaired regeneration. Psat1, a-KG, and glutamine were reduced in MuSCs of old mice and myoblasts of old individuals. a-KG or glutamine re-established appropriate muscle regeneration of adult Psat1-/- mice, old mice, and improved proliferation of old human myoblasts. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest a-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.
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