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| Status |
Public on Aug 03, 2022 |
| Title |
Glutamate pathway dysfunction in MELAS syndrome is alleviated by ketogenic diet |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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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| Overall design |
gene expression profiling of neuronal cells for 8 samples in two groups, control and Mutant.
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| Contributor(s) |
Dumont F, Goudenège D |
| Citation(s) |
35884972 |
| Submission date |
Feb 01, 2021 |
| Last update date |
Aug 04, 2022 |
| Contact name |
Florent Dumont |
| E-mail(s) |
florent.dumont@u-psud.fr
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| Organization name |
Université Paris-Saclay
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| Street address |
17 avenue des sciences
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| City |
91400 Orsay |
| State/province |
Ile de France |
| ZIP/Postal code |
91400 |
| Country |
France |
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| Platforms (1) |
| GPL6884 |
Illumina HumanWG-6 v3.0 expression beadchip |
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| Samples (8)
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| GSM5058862 |
control neuronal cells culture with DMEM (s1_Ctrl) |
| GSM5058863 |
100% mutant control neuronal cells culture with DMEM (s3_98 Mt) |
| GSM5058864 |
control neuronal cells culture with DMEM (s4_Ctrl) |
| GSM5058865 |
100% mutant control neuronal cells culture with DMEM (s6_98 Mt) |
| GSM5058866 |
control neuronal cells culture with DMEM (s7_Ctrl) |
| GSM5058867 |
100% mutant control neuronal cells culture with DMEM (s9_98 Mt) |
| GSM5058868 |
control neuronal cells culture with DMEM (s10_Ctrl) |
| GSM5058869 |
100% mutant control neuronal cells culture with DMEM (s12_98 Mt) |
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| Relations |
| BioProject |
PRJNA698639 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE165953_RAW.tar |
8.5 Mb |
(http)(custom) |
TAR (of IDAT) |
| Processed data included within Sample table |
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