MELAS syndrome causes glutamate and tricarboxylic acid cycle dysfunctions alleviated by ketone body treatment - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares Accéder directement au contenu
Article Dans Une Revue Biomedicines Année : 2022

MELAS syndrome causes glutamate and tricarboxylic acid cycle dysfunctions alleviated by ketone body treatment

Rayane Benyahia
  • Fonction : Auteur
Selma Kane
  • Fonction : Auteur
Tamas Aranyi
Aurore Inisan
  • Fonction : Auteur
Aurélie Renaud
  • Fonction : Auteur
Dominique Bonneau
  • Fonction : Auteur
Arnaud Chevrollier
Vincent Procaccio

Résumé

(1) Background: The development of mitochondrial medicine has been severely impeded by a lack of effective therapies. (2) Methods: To better understand Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-like episodes (MELAS) syndrome, neuronal cybrid cells carrying different mutation loads of the m.3243A > G mitochondrial DNA variant were analysed using a multi-omic approach. (3) Results: Specific metabolomic signatures revealed that the glutamate pathway was significantly increased in MELAS cells with a direct correlation between glutamate concentration and the m.3243A > G heteroplasmy level. Transcriptomic analysis in mutant cells further revealed alterations in specific gene clusters, including those of the glutamate, gamma-aminobutyric acid pathways, and tricarboxylic acid (TCA) cycle. These results were supported by post-mortem brain tissue analysis from a MELAS patient, confirming the glutamate dysregulation. Exposure of MELAS cells to ketone bodies significantly reduced the glutamate level and improved mitochondrial functions, reducing the accumulation of several intermediate metabolites of the TCA cycle and alleviating the NADH-redox imbalance. (4) Conclusions: Thus, a multi-omic integrated approach to MELAS cells revealed glutamate as a promising disease biomarker, while also indicating that a ketogenic diet should be tested in MELAS patients.
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Dates et versions

hal-03861087 , version 1 (19-11-2022)

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Sophie Belal, David Goudenège, Cinzia Bocca, Florent Dumont, Juan Manuel Chao de la Barca, et al.. MELAS syndrome causes glutamate and tricarboxylic acid cycle dysfunctions alleviated by ketone body treatment. Biomedicines, 2022, 10 (7), pp.1665. ⟨10.3390/biomedicines10071665⟩. ⟨hal-03861087⟩
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