The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes
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ABSTRACT:
PROVIDER: PRJNA741986 | ENA |
REPOSITORIES: ENA
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Project description:The goal of this study was to apply Next Generation Sequencing analyses to identify genes and pathways regulated by the Foxp1 transcription factor in 3T3-L1 adipocytes. We found, that series of genes involved in metabolism, glycolysis, signal transduction, as well as nervous system development are regulated in response to overexpression and knock down of this transcription factor, thereby providing important insight into biological role of Foxp1 for cells survival and metabolism.
2023-05-05 | GSE179031 | GEO
Project description:Understanding the mechanisms of the Warburg shift to aerobic glycolysis is central to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by bi-allelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed of the mitochondrial in tumors from HLRCC patients. Biochemical and transcriptomics analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of expression of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
2021-01-22 | GSE157256 | GEO
Project description:This study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes Th1 cell differentiation. P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-polarized CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, ATP synthase blockade in vitro and the consequent inhibition of oxidative phosphorylation, which forces cells to use aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 cell differentiation and suggest that ATP synthase inhibition is a fundamental mechanism by which P2X7 signaling induces the Th1 response.
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Project description:As the efficient therapeutic treatment for osteoporosis, Wnt signaling is considered to induce bone formation through aerobic glycolysis. However, the mechanism underlying the regulatory role of Wnt in orchestrating glucose metabolism during osteogenesis remains unclear. O-GlcNAcylation, a dynamic posttranslational modification (PTM) on proteins, controls multiple critical biological processes including gene transcription, translation, and cell fate determination. Here, we report Wnt3a either induces O-GlcNAcylation rapidly via the Ca2+-PKA-Gfat1 axis, or increases it in a Wnt-β-catenin dependent manner during prolonged stimulation. Importantly, O-GlcNAcylation is found indispensable for osteoblastogenesis both in vivo and in vitro. Genetic ablation of O-GlcNAcylation in osteoblast-lineage cells diminishes bone formation and delays bone fracture healing in response to Wnt stimulation. Notably, Wnt3a-induced O-GlcNAcylation enhances aerobic glycolysis by stabilizing PDK1 partially through Serine 174 (S174) site, which consequently facilitates osteogenesis. These findings highlight that O-GlcNAcylation is indispensable in Wnt-induced glucose metabolism during osteogenesis, indicating its potential as a therapeutic target for osteoporosis.
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Project description:Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknow. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons as a metabolic substrate contributing to fulfill their elevated energy requirements.
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Project description:Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
2024-04-25 | PXD048041 | Pride
Project description:Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
2024-04-25 | PXD048018 | Pride