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

Abstract

(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.

Gastrointestinal complications of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome managed by parenteral nutrition

“…It could explain concomitant occurrence of stroke -such as episodes and IPO [9] . The study by Belal et al [12] has revealed glutamate as a promising biomarker of disease severity. Metabolisation through the glutamate pathway was significantly increased in the cells from individuals affected by MELAS, with direct correlation between its concentration and the heteroplasmy level.…”

Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse

“…In addition, the higher GABA levels in the Hq cerebellum could also by explained by an enhanced neurotransmitter synthesis by the glutamate decarboxylase enzyme, as an attempt to increase succinate production to feed complex II, bypassing complex I and promoting ATP synthesis [ 60 , 61 , 62 ]. Of note, novel alterations in three key clusters of genes and cellular functions encompassing glutamate, glutamine, GABA metabolism and the Krebs cycle have been recently described in MELAS cybrids, changes that can be partially mitigated by a Krebs cycle anaplerosis with ketones [ 63 ]. These results support that in some MD, the mitochondrial defect leads to a Krebs cycle blockade and compensatory mechanisms involving glutamate and GABA.…”

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems

“…Anaerobic glycolysis often occurs in occasions when the regeneration of ATP in mitochondria is insufficient to meet the requirement, such as ischemia, hypoxia, or mitochondrial dysfunction 45 . Indeed, in mitochondrial dysfunction conditions, the process of glucose catabolism is impaired, which affects the Krebs cycle and leads to the increase of anaerobic glycolysis, eventually resulting in lactate accumulation 46 . Therefore, lactate accumulation is a key indicator of increasing anaerobic glycolysis.…”

“…increase of anaerobic glycolysis, eventually resulting in lactate accumulation. 46 Therefore, lactate accumulation is a key indicator of increasing anaerobic glycolysis.…”