Data from: Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status

Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential −251 mV±9.7, p<0.0001) with an increased level of oxidation by ~9 mV compared to controls (−260 mV±6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at −242 mV±7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.

线粒体疾病与能量生成减少及氧化还原（redox）稳态失衡密切相关。谷胱甘肽（glutathione）在氧化还原信号转导及抵御细胞氧化损伤中发挥核心作用。为阐明线粒体功能障碍对机体内氧化还原状态的影响，并明确该影响随线粒体疾病亚型及临床严重程度的变化情况，本研究采用高灵敏度串联质谱分析法，对大队列线粒体疾病患者的全血还原型谷胱甘肽（GSH）与氧化型谷胱甘肽（GSSG）水平进行精准定量检测。谷胱甘肽氧化还原电位通过能斯特（Nernst）方程计算得到。与健康对照组（n=59）相比，线粒体疾病患者队列（n=58）整体呈现显著的氧化还原失衡：其氧化还原电位为-251 mV±9.7，较对照组（-260 mV±6.4）的氧化水平升高约9 mV，差异具有极显著统计学意义（p<0.0001）。该异常的分子基础为：与对照组相比，线粒体疾病患者的全血GSH水平（p=0.0008）及GSH/GSSG比值（p=0.0002）显著降低，而GSSG水平（p<0.0001）显著升高。所有线粒体疾病亚组均呈现显著的氧化程度升高，包括Leigh综合征（Leigh syndrome，n=15）、电子传递链异常（n=10）、线粒体脑肌病伴高乳酸血症和卒中样发作（n=8）、线粒体DNA（mtDNA）缺失综合征（n=7）、线粒体DNA（mtDNA）耗竭综合征（n=7）及其他各类线粒体疾病（n=11）。因代谢危象住院的患者（n=7）氧化还原失衡程度最为显著，其氧化还原电位为-242 mV±7。外周全血GSH及GSSG水平有望成为线粒体功能障碍的潜在生物标志物，可为阐明氧化应激在各类线粒体疾病病理生理过程中的作用提供新思路。具体而言，氧化还原电位的检测或可用于临床状态监测，或在临床试验中评估患者对氧化还原调节治疗的响应情况。