Identification of hyperammonemia-induced changes in the cerebral transcriptome and proteome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE159625 | GEO | 2022/01/15
REPOSITORIES: GEO
Similar Datasets
Project description:Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. An ornithine transcarbamylase defect (Otcspf-ash) mouse model, a model of urea cycle disorder, was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (Gls2) or glutamine dehydrogenase 1 (Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. Reduced hepatic expression of Gls2, but not Glud1, by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia, reduced body weight loss, and reduced lethality. These data suggest that Gls2 hepatic knockdown could help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.
2022-06-07 | GSE179342 | GEO
Project description:Ammonia is a cytotoxic metabolite with pleotropic molecular and metabolic effects in non-hepatic tissue/cells targeting mitochondrial oxidative function that may contribute to post-mitotic senescence. Global molecular responses were determined by analysis of unbiased data followed by experimental validation of critical functional consequences in hyperammonemic differentiated myotubes and skeletal muscle from the portacaval anastomosis (PCA) rat. Integrating whole cell transcriptome with whole cell and mitochondrial proteome from hyperammonemic myotubes identified oxidative dysfunction and senescence pathways as being the most enriched with differentially expressed genes/proteins. Hyperammonemia and ammonia-lowering result in distinct clusters of molecular responses. Functional and metabolic studies in hyperammonemic myotubes showed that defects in electron transport chain (ETC) complexes I and III, loss of supercomplex assembly, decreased ATP synthesis, increased free radical generation with oxidative modification of proteins/lipids and increased expression of senescence associated molecular phenotype (SAMP) that were partially reversed by ammonia lowering. Studies in muscle from PCA rats established physiological relevance of our cellular studies. Dysregulated ammonia metabolism causes mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways that result in reversible senescence.
2022-02-17 | PXD026955 | Pride
Project description:Perturbed metabolism of ammonia, an endogenous cytotoxic molecule, causes mitochondrial dysfunction with decreased nicotinamide adenine dinucleotide (NAD+) in skeletal muscle. Consistent with our previous report of enrichment of NAD metabolism and sirtuin pathways during hyperammonemia, NAD+-dependent Sirtuin3 (Sirt3) expression and deacetylase activity weredecreased with increased muscle protein acetylation in murine and human skeletal muscle/myotubes. Acetylomics and cell fractions showed hyperammonemia-induced hyperacetylation of critical mitochondrial and signaling molecules. Overexpression of mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) reversed ammonia-induced oxidative dysfunction, electron transport chain (ETC) supercomplex disassembly, lower ATP content, NAD+, and redox ratio (NAD+/NADH). Protein hyperacetylation, post-mitotic senescence and lower mitochondrial sirtuin (Sirt3) expressionduring hyperammonemia were also reversed by MitoLbNOX. Sirt3 overexpression alone did not reverse ammonia-induced redox or mitochondrial dysfunction but reversed hyperacetylation and senescence. These data show that targeting redox ratio, rather than Sirt3, more consistently restores mitochondrial homeostasis and protein acetylation during hyperammonemia.
2023-10-24 | PXD033430 | Pride
Project description:Ammonia is a cytotoxic metabolite with pleotropic molecular and metabolic effects in non-hepatic tissue/cells targeting mitochondrial oxidative function that may contribute to post-mitotic senescence. Global molecular responses were determined by analysis of unbiased data followed by experimental validation of critical functional consequences in hyperammonemic differentiated myotubes and skeletal muscle from the portacaval anastomosis (PCA) rat. Integrating whole cell transcriptome with whole cell and mitochondrial proteome from hyperammonemic myotubes identified oxidative dysfunction and senescence pathways as being the most enriched with differentially expressed genes/proteins. Hyperammonemia and ammonia-lowering result in distinct clusters of molecular responses. Functional and metabolic studies in hyperammonemic myotubes showed that defects in electron transport chain (ETC) complexes I and III, loss of supercomplex assembly, decreased ATP synthesis, increased free radical generation with oxidative modification of proteins/lipids and increased expression of senescence associated molecular phenotype (SAMP) that were partially reversed by ammonia lowering. Studies in muscle from PCA rats established physiological relevance of our cellular studies. Dysregulated ammonia metabolism causes mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways with a distinct skeletal muscle SAMP.
2021-11-22 | PXD027754 | Pride
Project description:Nitrogen assimilation in plants is a tightly regulated process that integrates developmental and environmental signals. The legume-rhizobial symbiosis results in the formation of a specialized organ called root nodule, where the rhizobia fixes atmospheric nitrogen into ammonia. Ammonia is assimilated by the plant enzyme glutamine synthetase, which is specifically inhibited by PPT. The expression of key genes related to the regulation of root nodule metabolism will likely be affected by glutamine synthetase inhibition. We used microarrays to detail the global programme of gene expression in response to Glutamine synthetase inhibition in root nodules and identified genes differentially expressed over a time course.
2012-05-09 | GSE34155 | GEO
Project description:Ammonia is a toxic by-product of metabolism that causes cellular stress. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism that facilitate survival against toxicity have yet to be identified. We demonstrated that hypoxia-inducible factor-1α (HIF-1α) is stabilised and activated by ammonia stress. HIF-1α activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation and glutamine-dependent metabolism under ammonia stress in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1α counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1α in biphasic ammonia stress management in cancer stem-like cells. GS facilitates proliferation and HIF-1α contributes to metabolic remodelling in cellular energy usage resulting in attenuated proliferation but conversely promoting cell survival.
2017-11-22 | GSE107251 | GEO
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-28 | GSE171642 | GEO
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-28 | GSE171644 | GEO
Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.
2021-07-28 | GSE171643 | GEO
Project description:Identification of hyperammonemia-induced changes in the cerebral transcriptome and proteome
| PRJNA669876 | ENA