Glutathione deficiency in patients with mitochondrial disease: Implications for pathogenesis and treatment
Glutathione deficiency in patients with mitochondrial disease: Implications for pathogenesis and treatment
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DOI：
10.1007/s10545-005-4160-1
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Heales, SJR
中科院分区：
文献类型：
--
作者：
Hargreaves, IP;Sheena, Y;Heales, SJR
谷胱甘肽（GSH）是一种重要的细胞内抗氧化剂。就线粒体功能而言，GSH的丧失与电子传递链（ETC）受损有关。由于GSH的生物合成是一个能量依赖性过程，我们推测，在ETC缺陷的患者中，GSH状态受到损害，导致ETC活性的进一步丧失。我们进行了电化学HPLC分析，以确定24例骨骼肌活检的谷胱甘肽浓度与15个年龄匹配的疾病对照组相比，明确ETC缺陷的患者。这些组的比较显示，ETC缺乏组中GSH浓度显著降低（p < 0.001）：7.7 +/- 0.9 nmol/mg蛋白质vs对照组12.3 +/- 0.6 nmol/mg蛋白质。进一步的数据分析显示，与对照组相比，ETC有多重缺陷的患者具有最明显的GSH缺乏：4.1 +/- 0.9 nmol/mg蛋白（n = 4，p < 0.05）。这些研究结果表明，骨骼肌GSH浓度的不足与ETC缺陷有关，可能是ATP可用性降低或氧化应激增加的结果。因此，对抗氧化应激的能力降低可能导致ETC活性的进一步丧失，因此是这组疾病进行性的一个促成因素。此外，细胞GSH状态的恢复可能被证明是与他们的ETC缺陷相关的GSH缺乏症的患者的治疗益处。
Glutathione (GSH) is a key intracellular antioxidant. With regard to mitochondrial function, loss of GSH is associated with impairment of the electron transport chain (ETC). Since GSH biosynthesis is an energy-dependent process, we postulated that in patients with ETC defects GSH status becomes compromised, leading to further loss of ETC activity. We performed electrochemical HPLC analysis to determine the GSH concentration of 24 skeletal muscle biopsies from patients with defined ETC defects compared to 15 age-matched disease controls. Comparison of these groups revealed a significant (p < 0.001) decrease in GSH concentration in the ETC-deficient group: 7.7 +/- 0.9 vs 12.3 +/- 0.6 nmol/mg protein in the control group. Further analysis of the data revealed that patients with multiple defects of the ETC had the most marked GSH deficiency: 4.1 +/- 0.9 nmol/mg protein (n = 4, p < 0.05) when compared to the control group. These findings suggest that a deficiency in skeletal muscle GSH concentration is associated with an ETC defect, possibly as a consequence of diminished ATP availability or increased oxidative stress. The decreased ability to combat oxidative stress could therefore cause further loss of ETC activity and hence be a contributing factor in the progressive nature of this group of disorders. Furthermore, restoration of cellular GSH status could prove to be of therapeutic benefit in patients with a GSH deficiency associated with their ETC defects.