Introduction

The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell’s energy production. Strikingly, the m.3243A > G mutation is associated with different phenotypes, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD) and myopathy.

Objectives

We investigated urine metabolomes of MELAS, MIDD and myopathy patients in order to identify affected metabolic pathways and possible treatment options.

Methods

A multiplatform metabolomics approach was used to comprehensively analyze the metabolome and compare metabolic profiles of different phenotypes caused by the m.3243A > G mutation. Our analytical array consisted of NMR spectroscopy, LC-MS/MS and GC-TOF-MS.

Results

The investigation revealed phenotypic specific metabolic perturbations, as well as metabolic similarities between the different phenotypes. We show that glucose metabolism is highly disturbed in the MIDD phenotype, but not in MELAS or myopathy, remodeled fatty acid oxidation is characteristic of the MELAS patients, while one-carbon metabolism is strongly modified in both MELAS and MIDD, but not in the myopathy group. Lastly we identified increased creatine in the urine of the myopathy patients, but not in MELAS or MIDD.

Conclusion

We conclude by giving novel insight on the phenotypes of the m.3243A > G mutation from a metabolomics point of view. Directives are also given for future investigations that could lead to better treatment options for patients suffering from this debilitating disease.

中文翻译：

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一种突变，三种表型：对由 m.3243A > G 突变引起的 MELAS、MIDD 和肌病的新代谢见解

介绍

m.3243A>G线粒体DNA突变是最常见的线粒体致病突变之一，携带率高达1：400。这种点突变会影响 MT-TL1 基因，最终影响氧化磷酸化系统和细胞的能量产生。引人注目的是，m.3243A > G 突变与不同的表型相关，包括线粒体脑肌病、乳酸酸中毒和中风样发作 (MELAS)、母系遗传的糖尿病和耳聋 (MIDD) 和肌病。

目标

我们调查了 MELAS、MIDD 和肌病患者的尿液代谢组，以确定受影响的代谢途径和可能的治疗方案。

方法

多平台代谢组学方法用于综合分析代谢组并比较 m.3243A > G 突变引起的不同表型的代谢谱。我们的分析阵列由 NMR 光谱、LC-MS/MS 和 GC-TOF-MS 组成。

结果

调查揭示了表型特定的代谢扰动，以及不同表型之间的代谢相似性。我们表明葡萄糖代谢在 MIDD 表型中受到高度干扰，但在 MELAS 或肌病中没有，重塑的脂肪酸氧化是 MELAS 患者的特征，而一碳代谢在 MELAS 和 MIDD 中均发生强烈改变，但在肌病中没有团体。最后，我们发现肌病患者尿液中的肌酸增加，但在 MELAS 或 MIDD 中没有。

结论

最后，我们从代谢组学的角度对 m.3243A > G 突变的表型提供了新的见解。还为未来的调查提供了指示，这些调查可能会为患有这种使人衰弱的疾病的患者提供更好的治疗选择。