谷氨酸诱导的线粒体脑病乳酸酸中毒综合征中风样发作 (MELAS) 综合征中克雷布斯循环的失调通过酮体暴露得到缓解

Glutamate-induced deregulation of krebs cycle in mitochondrial encephalopathy lactic acidosis

syndrome stroke-like episodes (MELAS) syndrome is alleviated by ketone body exposure.

Keywords：MELAS syndrome, NADH/NAD imbalance, Glutamate, Ketone body treatment, Mitochondrial diseases, mtDNA, Multi-omics, Tricarboxylic acid cycle

关键词：MELAS 综合征、NADH/NAD 失衡、谷氨酸盐、酮体治疗、线粒体疾病、mtDNA、多组学、三羧酸循环

细胞系：神经母细胞瘤
作者：Belal Sophie, Goudenege David, Bocca Cinzia, Dumont Florent, Chao De La Barca Juan Manuel, Desquiret-Dumas Valerie, Gueguen Naig, Geffroy Guillaume, Benyahia Rayane, Kane Selma, Khiati Salim, Bris Celine, Aranyi Tamas, Stockholm Daniel, Inisan Aurore, Renaud Aurelie, Barth Magalie, Simard Gilles, Reynier Pascal, Letournel Franck, Lenaers Guy, Bonneau Dominique, Chevrollier Arnaud, Procaccio Vincent

出版期刊：《Biomedicines》（2022年7月11日）

Abstract：

The development of mitochondrial medicine has been severely impeded by a lack of effective therapies.
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.
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.
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. 

文章摘要：

由于缺乏有效的治疗方法，线粒体医学的发展受到了严重阻碍。
为了更好地了解线粒体脑病乳酸酸中毒综合征中风样发作 (MELAS) 综合征，使用多组学方法分析了携带不同突变负荷的 m.3243A > G 线粒体 DNA 变体的神经元胞质细胞。
特定的代谢组学特征表明，MELAS 细胞中的谷氨酸途径显着增加，谷氨酸浓度与 m.3243A > G 异质性水平之间存在直接相关性。突变细胞的转录组学分析进一步揭示了特定基因簇的改变，包括谷氨酸、γ-氨基丁酸途径和三羧酸 (TCA) 循环。这些结果得到了一名 MELAS 患者的尸检脑组织分析的支持，证实了谷氨酸失调。 MELAS 细胞暴露于酮体显着降低了谷氨酸水平并改善了线粒体功能，减少了 TCA 循环的几种中间代谢物的积累并减轻了 NADH-氧化还原失衡。
因此，对 MELAS 细胞的多组学整合方法揭示了谷氨酸作为一种有前途的疾病生物标志物，同时也表明应在 MELAS 患者中测试生酮饮食。

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