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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

ABSTRACT: 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

PROVIDER: PRJNA837596 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24653000_1.fastq.gz	Fastqsanger.gz
	SRR24653000_2.fastq.gz	Fastqsanger.gz
	SRR24653001_1.fastq.gz	Fastqsanger.gz
	SRR24653001_2.fastq.gz	Fastqsanger.gz
	SRR24653002_1.fastq.gz	Fastqsanger.gz

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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

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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

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

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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]

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