Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biomedicines Année : 2022

Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure

Sophie Belal
  • Fonction : Auteur
David Goudenège
Cinzia Bocca
  • Fonction : Auteur
Juan Manuel Chao de la Barca
Valérie Desquiret-Dumas
  • Fonction : Auteur
Naïg Gueguen
Guillaume Geffroy
  • Fonction : Auteur
Rayane Benyahia
  • Fonction : Auteur
Selma Kane
  • Fonction : Auteur
Salim Khiati
Céline Bris
  • Fonction : Auteur
Tamas Aranyi
Daniel Stockholm
Aurore Inisan
  • Fonction : Auteur
Aurélie Renaud
  • Fonction : Auteur
Magalie Barth
  • Fonction : Auteur
Gilles Simard
  • Fonction : Auteur
Pascal Reynier
Franck Letournel
  • Fonction : Auteur
Guy Lenaers
  • Fonction : Auteur
Dominique Bonneau
  • Fonction : Auteur
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.

Dates et versions

hal-04436403 , version 1 (03-02-2024)

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Sophie Belal, David Goudenège, Cinzia Bocca, Florent Dumont, Juan Manuel Chao de la Barca, et al.. Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure. Biomedicines, 2022, 10 (7), pp.1665. ⟨10.3390/biomedicines10071665⟩. ⟨hal-04436403⟩
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