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Chromatin accessibility and mitochondrial genotype from single cells of the retina and choroid in human MELAS (m.3243A>G) and control samples [scATAC-seq]

ABSTRACT: Chromatin accessibility and mitochondrial genotype from single cells of the retina and choroid in human MELAS (m.3243A>G) and control samples [scATAC-seq]

PROVIDER: PRJNA837213 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19169300_1.fastq.gz	Fastqsanger.gz
	SRR19169300_2.fastq.gz	Fastqsanger.gz
	SRR19169301_1.fastq.gz	Fastqsanger.gz
	SRR19169301_2.fastq.gz	Fastqsanger.gz
	SRR19169302_1.fastq.gz	Fastqsanger.gz

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Chromatin accessibility and mitochondrial genotype from single cells of the retina and choroid in human MELAS (m.3243A>G) and control samples [scATAC-seq]

Project description:The mitochondrial m.3243A>G variant is known to cause retinal dystrophy and vision loss. We used mitochondria single cell ATAC sequencing to measure nuclear chromatin accessibility and mitochondrial heteroplasmy in single cells of the retina and choroid.

2023-06-08 | GSE202746 | GEO

Differential expression of miRNAs in a cellular model of MELAS.

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

Gene expression from single cells of the retina and choroid in human MELAS (m.3243A>G) and control samples [scRNA-seq]

Project description:The mitochondrial m.3243A>G variant is known to cause retinal dystrophy and vision loss. We used single cell RNA sequencing to understand how the presence of this mutation affects cellular phenotype in a cell type-specific manner.

2023-06-08 | GSE202735 | GEO

Gene expression from single cells of the retina and choroid in human MELAS (m.3243A>G) and control samples [scRNA-seq]

Project description:Gene expression from single cells of the retina and choroid in human MELAS (m.3243A>G) and control samples [scRNA-seq]

| PRJNA837192 | ENA

Glutamate pathway dysfunction in MELAS syndrome is alleviated by ketogenic diet

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

Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons

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

Metabolic remodelling in hiPSC-derived myofibres carrying the m.3243A>G mutation

Project description:Mutations in mitochondrial DNA cause severe multisystem disease, frequently associated with muscle weakness. The m.3243A>G mutation is the major cause of Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke Like episodes (MELAS). Experimental models that recapitulate the disease phenotype in vitro for disease modelling or drug screening are very limited. We have therefore generated hiPSC-derived muscle fibres with variable heteroplasmic mtDNA mutation load without significantly affecting muscle differentiation potential. The cells are excitable and show physiological characteristics of muscle fibres and show well organised myofibrillar structure. In cells carrying the m.3243A>G, the mitochondrial membrane potential and oxygen consumption were reduced in relation to the mutant load. We have shown through proteomic, phosphoproteomic, and metabolomic analyses that the m.3243A>G mutation variably affects the cell phenotype in relation to the mutant load. This variation is reflected by an increase in the NADH/NAD+ ratio, which in turns influences key nutrient-sensing pathways in the myofibres. This model enables detailed study of the impact of the mutation on cellular bioenergetics and on muscle physiology with the potential to provide a platform for drug screening.

2025-05-26 | PXD058785 | Pride

Multimodal sequencing (gene expression, chromatin accessibility, and mtDNA genotyping) of single cells of the RPE and choroid in human MELAS (m.3243A>G) and control samples

Project description:The mitochondrial m.3243A>G variant is known to cause retinal dystrophy and vision loss. We used single cell multimodal sequencing to understand how the presence of this mutation affects cellular phenotype in a cell type-specific manner.

2023-06-08 | GSE202886 | GEO

Quantitative variation in m.3243A>G mutation produce discrete changes in energy metabolism

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

Mitochondrial 3243A > G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells

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

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