MondoA Links Muscle Lipid Accumulation and Insulin Resistance Driven by Nutrient Overload
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA523225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8590750.fastq.gz | Fastqsanger.gz | |||
| SRR8590751.fastq.gz | Fastqsanger.gz | |||
| SRR8591753.fastq.gz | Fastqsanger.gz | |||
| SRR8591754.fastq.gz | Fastqsanger.gz | |||
| SRR8591755.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-08-22 | GSE126767 | GEO
Project description:BACKGROUND: Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways and ATP levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor Rocaglamide A (RocA) induces Thioredoxin Interacting Protein (TXNIP). TXNIP is a negative regulator of glucose uptake, thus its induction by RocA links translation to the availability of glucose. MondoA is the principal regulator of glucose-induced transcription and its activity is triggered by the glycolytic intermediate, glucose 6-phosphate (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial ATP (mtATP), suggesting a critical role in the cellular response to these energy sources. TXNIP expression is entirely dependent on MondoA, therefore, we investigated how protein synthesis inhibitors impact its transcriptional activity. METHODS: We investigated how translation regulates MondoA activity using cell line models and loss-of-function approaches. We examined how protein synthesis inhibitors effect gene expression and metabolism using RNA-sequencing and metabolomics, respectively. The biological impact of RocA was evaluated using both cell line models and Patient-Derived Xenograft Organoid models. RESULTS: We discovered that multiple protein synthesis inhibitors, including RocA, increase TXNIP expression in a manner that depends on MondoA, a functional electron transport chain and mtATP synthesis. Furthermore, RocA increases mtATP and G6P levels and TXNIP induction depends on interactions between the Voltage-Dependent Anion Channel (VDAC) and hexokinase, which generates G6P. RocA treatment impacts the regulation of ~1200 genes and ~250 of those genes are MondoA-dependent. RocA treatment is cytotoxic to Triple Negative Breast Cancer cell lines and shows preferential cytotoxicity against ER- patient-derived breast cancer models. Finally, RocA-driven cytotoxicity is partially-dependent on MondoA or TXNIP. CONCLUSION: Our data suggest that protein synthesis inhibitors rewire metabolism, resulting in an increase in mtATP and G6P, the latter driving MondoA-dependent transcriptional activity. Further, MondoA is a critical component of the cellular transcriptional response to RocA. Our functional assays suggest that RocA or similar translation inhibitors may show efficacy against ER- tumors and that the levels of MondoA and TXNIP should be considered when exploring these potential treatment options.
2020-12-07 | GSE153499 | GEO
Project description:Leishmania TORC1 links nutrient availability to differentiation into infective
2022-10-31 | MSV000090621 | MassIVE
Project description:Obesity-related insulin resistance is associated with intramyocellular lipid accumulation in skeletal muscle. We hypothesized that in contrast to current dogma, this linkage is related to an upstream mechanism that coordinately regulates both processes. We demonstrate that the muscle-enriched transcription factor MondoA is glucose/fructose responsive in human skeletal myotubes and directs the transcription of genes in cellular metabolic pathways involved in diversion of energy substrate from a catabolic fate into nutrient storage pathways including fatty acid desaturation and elongation, triacylglyeride (TAG) biosynthesis, glycogen storage, and hexosamine biosynthesis. MondoA also reduces myocyte glucose uptake by suppressing insulin signaling. Mice with muscle-specific MondoA deficiency were partially protected from insulin resistance and muscle TAG accumulation in the context of diet-induced obesity. These results identify MondoA as a nutrient-regulated transcription factor that under normal physiological conditions serves a dynamic checkpoint function to prevent excess energy substrate flux into muscle catabolic pathways when myocyte nutrient balance is positive. However, in conditions of chronic caloric excess, this mechanism becomes persistently activated leading to progressive myocyte lipid storage and insulin resistance.
| S-EPMC6693825 | biostudies-literature
Project description:Human MondoA requires glucose as well as other modulatory signals to function in transcription. One such signal is acidosis, which increases MondoA activity and also drives a protective gene signature breast cancer. How low pH controls MondoA transcriptional activity is unknown. We found that low pH medium increases mitochondrial ATP (mtATP), which is subsequently exported from the mitochondrial matrix. Mitochondria-bound hexokinase transfers a phosphate from mtATP to cytoplasmic glucose to generate glucose-6-phosphate (G6P), which is an established MondoA activator. The outer mitochondrial membrane localization of MondoA suggests that it is positioned to coordinate the adaptive transcriptional response to a cell’s most abundant energy sources, cytoplasmic glucose and mtATP. In response to acidosis, MondoA shows preferential binding to just two targets, TXNIP and its paralog ARRDC4. Because these transcriptional targets are suppressors of glucose uptake we propose that MondoA is critical for restoring metabolic homeostasis in response to high energy charge.
2019-01-23 | GSE125089 | GEO
Project description:In order to investigate the effect of MondoA loss on the expression of Myc-dependent genes, we performed a microarray analysis from RNAs isolated from TET21N cells expressing either control (siControl) or MondoA (siMondoA) siRNAs either with (NT) or without (Doxy) induced N-Myc expression. TET21N cells were grown in medium with either Doxy (Myc-Off) or No Treatment (Myc-On), then transiently transfected with either non-specific siRNA or MondoA siRNA in replicates. Cells were then lysed and RNA isolated.
2015-01-01 | E-GEOD-55538 | biostudies-arrayexpress
Project description:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. To identify novel candidates for targeted treatment of childhood ALL, we performed a comprehensive transcriptome analysis yielding a set of genes specifically overexpressed in ALL. Among them we identified MondoA - a transcription factor regulating glycolysis in response to glucose availability. Here, we confirm that MondoA is highly overexpressed ALL, whereas the MondoA paralog, MondoB, is not expressed. Expression studies revealed that MondoA is not regulated by glucose availability in leukemia cells, but by the presence of lactate. An in silico MondoA promoter analysis identified two methylation-prone CpG-islands and four conserved binding sites for runt-related transcription factor 1 (RUNX1). In fact, MondoA and RUNX1 are significantly coexpressed in leukemia and experimental blockage of DNA methylation leads to a further induction of MondoA. In addition, using microarray profiling, gene-set enrichment analysis and RNA interference we provide for the first time evidence that MondoA expression not only increases glucose catabolism, but also maintains a more immature ALL phenotype, which is associated with enhanced survival and clonogenicity of leukemia cells. These data hint to an important contribution of MondoA to leukemia aggressiveness validating MondoA as an attractive candidate for targeted treatment of ALL. Two nonsense shRNA expressing control Nalm6 clones and three MondoA shRNA expressing Nalm6 clones were subjected to microarray analysis.
2012-07-31 | E-GEOD-33967 | biostudies-arrayexpress
Project description:To determine the contibution of the transcription factor MondoA to 2-deoxyglucose-induced transcription expression analysis was carried out in control and MondoA knockdown cells HA1ER cells are human embryonic kidney cells transformed with hTERT, SV40 Early region and activated H-Ras Keywords: cell type comparision, genetic modification HA1ER cells, Control (NS) or MondoA knockdown (M2), were starved for glucose overnight and then treated with 2-deoxyglucose for 3 hours
2008-04-24 | E-GEOD-11242 | biostudies-arrayexpress
Project description:The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we have revealed an unexpected role of this pathway in vertebrate embryonic development. We characterized Mondo pathway function in the zebrafish and showed that knock-down of mondoa impaired the early morphogenetic movement of epiboly in zebrafish embryos. Expression of nsdhl , an enzyme of cholesterol and pregnenolone synthesis, was strongly reduced in these embryos. Loss of Nsdhl function likewise impaired epiboly and led to microtubule cytoskeleton defects in the embryo, similar to MondoA loss of function. Both epiboly and microtubule cytoskeleton defects were partially restored by pregnenolone treatment. Gene disruption of mondoa perturbed epiboly with only partial penetrance, likely due to compensatory changes in the expression of cholesterol/steroid metabolism genes. Collectively, our results show a novel role for MondoA in the regulation of early vertebrate development, connecting glucose, cholesterol and steroid hormone metabolism with early embryonic cell movements.
2020-09-11 | GSE144349 | GEO
Project description:The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we have revealed an unexpected role of this pathway in vertebrate embryonic development. We characterized Mondo pathway function in the zebrafish and showed that knock-down of mondoa impaired the early morphogenetic movement of epiboly in zebrafish embryos. Expression of nsdhl , an enzyme of cholesterol and pregnenolone synthesis, was strongly reduced in these embryos. Loss of Nsdhl function likewise impaired epiboly and led to microtubule cytoskeleton defects in the embryo, similar to MondoA loss of function. Both epiboly and microtubule cytoskeleton defects were partially restored by pregnenolone treatment. Gene disruption of mondoa perturbed epiboly with only partial penetrance, likely due to compensatory changes in the expression of cholesterol/steroid metabolism genes. Collectively, our results show a novel role for MondoA in the regulation of early vertebrate development, connecting glucose, cholesterol and steroid hormone metabolism with early embryonic cell movements.
2020-09-11 | GSE134778 | GEO