Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status.
Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status.
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DOI：
10.1371/journal.pone.0100001
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Cowan TM
中科院分区：
文献类型：
--
作者：
Enns GM;Moore T;Le A;Atkuri K;Shah MK;Cusmano-Ozog K;Niemi AK;Cowan TM
线粒体疾病与能量产生减少和氧化还原失衡有关。谷氨酸在氧化还原信号传导和保护细胞免受氧化损伤中起核心作用。为了了解线粒体功能障碍对体内氧化还原状态的影响，并确定线粒体疾病亚型和临床严重程度如何变化，我们使用了灵敏的串联质谱分析法来精确定量一个大型线粒体疾病患者队列中全血还原型（GSH）和氧化型（GSSG）谷胱甘肽水平。使用Nernst方程计算谷氨酸的氧化还原电位。与健康对照组（n = 59）相比，线粒体疾病患者（n = 58）作为一个组显示出显著的氧化还原失衡（氧化还原电位-251 mV±9.7，p<0.0001），与对照组（-260 mV±6.4）相比，氧化水平增加了0.9mV。 与对照组相比，线粒体疾病患者的全血GSH水平（p = 0.0008）和GSH/GSSG比值（p =0.0002）显著降低，而GSSG水平显著升高（p<0.0001）。 在所有线粒体疾病亚组中，氧化还原电位显著更高，包括Leigh综合征（n = 15）、电子传递链异常（n = 10）、线粒体脑肌病、乳酸酸中毒和卒中样发作（n = 8）、mtDNA缺失综合征（n = 7）、mtDNA耗竭综合征（n = 7）和其他线粒体疾病（n = 11）。 因代谢危象住院的患者（n = 7）在−242 mV±7时表现出最大程度的氧化还原失衡。 外周全血GSH和GSSG水平是线粒体功能障碍的有前途的生物标志物，并可能提供见解的各种线粒体疾病的病理生理学的氧化应激的贡献。特别是，氧化还原电位的评估可能有助于监测临床状态或临床试验中对氧化还原调节疗法的反应。
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.
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影响因子：
4.8
作者：
Makino, Y;Yoshikawa, N;Tanaka, H
通讯作者：
Tanaka, H
DOI：
10.1016/j.bbamcr.2012.06.019
发表时间：
2012-10
影响因子：
5.1
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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