Mitochondrial 3243A > G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells
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PROVIDER: PRJNA524862 | ENA |
REPOSITORIES: ENA
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Project description:We obtained three independent sets of endothelial cells differentiated from iPSCs derived from a Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patient as well as iPSCs that has been corrected for the mitochondrial mutation.
2019-10-29 | GSE127478 | GEO
Project description: Not available
| S-EPMC6805858 | biostudies-other
Project description:We investigate the participation of miRNAs in the cell response to the mitochondrial dysfunction associated with m.3243A>G mutation in mitochondrial DNA (mtDNA), which is the most common cause of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome.Through small-RNA sequencing and in silico analysis, we identified 246 differentially-expressed in a transmitochondrial cybrid model of MELAS (100% m.3243A>G mutant mitochondrial DNA), with 126 being up-regulated and 120 down-regulated. The enrichment analysis of Gene Ontology (GO) terms revealed that target genes for dysregulated miRNAs were involved in muscle and nervous system development, heart development, and signaling pathways controlling cardiac events.These data suggest that the miRNA program triggered by the MELAS m.3243A>G mutation could explain for some of the clinical manifestations of the MELAS syndrome.
2019-03-29 | GSE113300 | GEO
Project description:The development of mitochondrial medicine is greatly impaired by the lack of knowledge and identification of efficient therapeutic routes targeting mitochondria. To better understand the pathophysiology of MELAS syndrome, neuronal cybrid cells, carrying different mutant loads of the m.3243A>G mutation, were investigated by a metabolomics and transcriptomics combined approach. Specific signatures, identifying MELAS biochemical biomarkers, disclosed the glutamate pathway as a culprit mechanism, establishing a strong correlation between glutamate concentrations and the m.3243A>G heteroplasmy levels. Transcriptomic analyses further revealed peculiar gene clusters, including glutamate, gamma-aminobutyric acid (GABA) and tricarboxylic acid (TCA) cycle pathways. These results were supported by post-mortem brain tissue analysis of a MELAS patient, confirming the dysregulation of the glutamate metabolic pathway. Ketogenic diet known to reduce glutamate toxicity, induced a significant reduction of glutamate level after 48h of ketone body treatment, improved mitochondrial functions alleviating the accumulation of several intermediate metabolites of the TCA cycle in MELAS cells. Thus, the integrated approach using a multi-OMICs strategy on MELAS cybrid cells, disclosed novel insights in the mitochondrial energy failure, identifying glutamate as a potential biomarker of the disease, while highlighting ketogenic diet, a nutrition based strategy, to treat MELAS patients
2022-08-03 | GSE165953 | GEO
Project description:Regulation of coding and non-coding genes is studied from primary human aortic endothelial cells (HAECs), venous endothelial cells (HUVECs), aortic smooth muscle cells (HASMCs) and macrophages (CD14+) under pro-atherogenic stimuli (hypoxia, oxPAPC and hypoxia+oxPAPC) by integrating three different sequencing techinques: GRO-seq, miRNA-seq and RNA-seq
2020-06-17 | GSE136813 | GEO
Project description:Background: The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the MELAS syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. Objective: To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. Methods: Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. Results and Interpretation: Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1α (HIF-1α)/HIF-1β complex, nuclear factor Y (NF-Y) and CREB-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome. Peripheral blood samples were collected from ten A3243G MELAS patients and twenty age- and sex-matched healthy controls (2 controls for each patient). The patient cohort consisted of 4 females and 6 males, mean±s.e.m. age was 44.1±11.9 years (range: 22–63 years), mean±s.e.m. age at disease onset was 27.1±4.9 years (range: 13–55 years), mean±s.e.m. disease duration was 19.0±4.7 years (range: 4–43 years), and disease severity measured by the ‘Newcastle Mitochondrial Disease Adult Scale’ (NMDAS) 8 ranging from 0.0 (no symptoms) to 1.0 (maximum score) was 0.26±0.05 (range: 0.02–0.54).
2011-01-24 | E-GEOD-14882 | biostudies-arrayexpress
Project description:Pathenogenesis of atherosclerosis results from the interactions between disrupted lipid homeostasis and immune response, but the molecular bridges between the major players are still a matter of controversy. We performed a systemic study of the imflammatory cytokine tumor necrosis factor alpha (TNF alpha), a well established anorexia agent, in the livers of the mice exposed to 20h-cytokine/starvation. We show that treatment with TNF-alpha reverses adaptations to fasting. Moreover, it up-regulates cholesterol biosynthesis and down-regulates bile acids synthesis, which leads to disrupted cholesterol homeostasis and pro-atherogenic changes. Interestingly, we found that TNF alpha also interferes with gene regulation of the xenobiotic metabolism. Keywords: treatment and diet effects Mice have been either saline treated (nontreated group), saline treated and fasted for 20h (fasted group), and TNF-alpha treated (30 mikrograms per animal) and fasted for 20h (TNF-alpha group). 3 biological replicas from fasted and TNF-alpha groups were co-hybridized with pool of nontreated group. No dye-swaps were performed.
2010-05-25 | E-GEOD-6423 | biostudies-arrayexpress