Identification of miRNA, lncRNA and mRNA-associated ceRNA networks and potential biomarker for MELAS with mitochondrial DNA A3243G mutation [array]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89059 | GEO | 2016/10/23
SECONDARY ACCESSION(S): PRJNA350209
REPOSITORIES: GEO
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Project description:To elucidate the regulating networks of dysregulated ncRNAs in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) with m.A3243G mutation.
2016-10-23 | GSE89065 | GEO
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: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 expression of mitochondrially-encoded genes requires the efficient processing of long precursor RNAs at the 5´ and 3´ ends of tRNAs, a process which, when disrupted, results in disease. Two such mutations reside within mt-tRNALeu(UUR); a m.3243A>G transition, which is the most common cause of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), and m.3302A>G which often causes mitochondrial myopathy (MM). We used parallel analysis of RNA ends (PARE) that captures the 5´ terminal end of 5´-monophosphorylated mitochondrial RNAs to compare the effects of the m.3243A>G and m.3302A>G mutations on mitochondrial tRNA processing. We confirmed previously identified RNA processing defects, identified common internal cleavage sites and new sites unique to the m.3243A>G mutants that do not correspond to transcript ends. These sites occur in regions of predicted RNA secondary structure, or are in close proximity to such regions, and may identify regions of importance to the processing of mtRNAs.
2017-03-23 | GSE85549 | GEO
Project description:MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical heterogeneity and the obscure genotype-phenotype correlation among MELAS patients. To gain insights into the pathogenic signature of MELAS, we designed a comprehensive strategy integrating proteomics and metabolomics in patient-derived dermal fibroblasts harboring the ultra-rare MELAS pathogenic variant m.14453G>A, specifically affecting the mitochondrial respiratory complex I. Global proteomics was achieved by data-dependent acquisition (DDA) and verified by data-independent acquisition (DIA) using both Spectronaut and the recently launched MaxDIA platforms. Comprehensive metabolite coverage was achieved for both polar and nonpolar metabolites in both reverse phase and HILIC LC-MS/MS analyses. Our proof-of-principle MELAS study with multi-omics integration revealed OXPHOS dysregulation with a predominant deficiency of complex I subunits, as well as alterations in key bioenergetic pathways, glycolysis, tricarboxylic acid cycle, and fatty acid ?-oxidation. The most clinically relevant discovery is the downregulation of the arginine biosynthesis pathway, likely due to blocked argininosuccinate synthase, which is congruent with the MELAS cardinal symptom of stroke-like episodes and its current treatment by arginine infusion. In conclusion, we demonstrated an integrated proteomic and metabolomic strategy for patient-derived fibroblasts, which has great clinical potential to discover therapeutic targets and design personalized interventions after validation with a larger patient cohort in the future.
2021-10-16 | MSV000088237 | MassIVE
Project description:Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is often caused by an adenine to guanine variant at m.3243 (m.3243A>G) of the MT-TL1 gene. To understand how this pathogenic variant affects the nervous system, we differentiated human induced pluripotent stem cells (iPSCs) into excitatory neurons with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function from MELAS patients with the m.3243A>G pathogenic variant. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found reduced expression of genes involved in mitochondrial respiration and presynaptic function, as well as non-cell autonomous processes in co-cultured astrocytes. Finally, we show that the clinical phase II drug sonlicromanol can improve neuronal network activity when treatment is initiated early in development. This was intricately linked with changes in the neuronal transcriptome. Overall, we provide insight in transcriptomic changes in iPSC-derived neurons with high m.3243A>G heteroplasmy, and show the pathology is partially reversible by sonlicromanol.
2021-07-29 | GSE154825 | GEO
Project description:MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical heterogeneity and the obscure genotype-phenotype correlation among MELAS patients. To gain insights into the pathogenic signature of MELAS, we designed a comprehensive strategy integrating proteomics and metabolomics in patient-derived dermal fibroblasts harboring the ultra-rare MELAS pathogenic variant m.14453G>A, specifically affecting the mitochondrial respiratory complex I. Global proteomics was achieved by data-dependent acquisition (DDA) and verified by data-independent acquisition (DIA) using both Spectronaut and the recently launched MaxDIA platforms. Comprehensive metabolite coverage was achieved for both polar and nonpolar metabolites in both reverse phase and HILIC LC-MS/MS analyses. Our proof-of-principle MELAS study with multi-omics integration revealed OXPHOS dysregulation with a predominant deficiency of complex I subunits, as well as alterations in key bioenergetic pathways, glycolysis, tricarboxylic acid cycle, and fatty acid ?-oxidation. The most clinically relevant discovery is the downregulation of the arginine biosynthesis pathway, likely due to blocked argininosuccinate synthase, which is congruent with the MELAS cardinal symptom of stroke-like episodes and its current treatment by arginine infusion. In conclusion, we demonstrated an integrated proteomic and metabolomic strategy for patient-derived fibroblasts, which has great clinical potential to discover therapeutic targets and design personalized interventions after validation with a larger patient cohort in the future.
2021-10-16 | MSV000088237 | GNPS
Project description:To understand the effect of lactic acidosis in cholangiocarcinoma cell line. Cells were cultured in different conditions: lactic acidosis, lactosis, acidosis and control. We found that lactic acidosis promoted aggressiveness of cancer cells and reprograming of metabolic.
2022-10-12 | GSE215085 | GEO
Project description:[1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for different length of time. We used microarrays to examine the genomic programs of cells incubated under lactic acidosis for different length of time [2] Metabolic profiling: MCF7 cells were exposed to control condition, 25mM lactic acidosis, glucose deprivation (zero glucose) and hypoxia (1% oxygen level). [3] Mouse study: Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. Wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs and the RNAs from cells were extracted with MiRVana kit (Ambion) and applied to Affymetrix 430A mouse chips We used microarrays to examine the genomic programs of cells incubated under different microenvironmental stresses. [1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for 1, 4, 12 and 24 hours. [2] Metabolic profiling: MCF7 cells were exposed to lactic acidosis, glucose deprivation and hypoxia for 4hours. [3] wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs.
2010-09-27 | E-GEOD-19123 | biostudies-arrayexpress
Project description:Mitochondrial DNA (mtDNA) 3243A>G tRNALeu(UUR) heteroplasmic mutation (m.3243A>G) exhibits clinically heterogeneous phenotypes. While the high mtDNA heteroplasmy exceeding a critical threshold causes mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome, the low mtDNA heteroplasmy causes maternally inherited diabetes with or without deafness (MIDD) syndrome. How quantitative differences in mtDNA heteroplasmy produces distinct pathological states has remained elusive. Here we show that despite striking similarities in the energy metabolic gene expression signature, the mitochondrial bioenergetics, biogenesis and fuel catabolic functions are distinct in cells harboring low or high levels of the m.3243A>G mutation compared to wild type cells. We further demonstrate that the low heteroplasmic mutant cells exhibit a coordinate induction of transcriptional regulators of the mitochondrial biogenesis, glucose and fatty acid metabolism pathways that lack in near homoplasmic mutant cells compared to wild type cells. Altogether, these results shed new biological insights on the potential mechanisms by which low mtDNA heteroplasmy may progressively cause diabetes mellitus.
2019-04-09 | GSE129091 | GEO