Treatment of CoQ10 Deficient Fibroblasts with Ubiquinone, CoQ Analogs, and Vitamin C: Time- and Compound-Dependent Effects
Treatment of CoQ10 Deficient Fibroblasts with Ubiquinone, CoQ Analogs, and Vitamin C: Time- and Compound-Dependent Effects
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DOI：
10.1371/journal.pone.0011897
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发表时间：
2010-07-30
期刊：
影响因子：
3.7
通讯作者：
Hirano, Michio
中科院分区：
文献类型：
--
作者：
Lopez, Luis C.;Quinzii, Catarina M.;Hirano, Michio
背景资料：辅酶Q（10）（CoQ（10））及其类似物凭借其作为电子载体、抗氧化剂化合物或两者的功能而在治疗上使用。然而，已发表的研究表明，不同的泛醌类似物可能会产生不同的影响氧化磷酸化和oxidative stress.Methodology/主要发现：为了测试这些概念，我们已经评估了辅酶Q（10），辅酶Q（2）（辅酶Q（2）），艾地苯醌，维生素C对生物能量学和氧化应激在人皮肤成纤维细胞与主要辅酶Q（10）缺乏症的影响。每种化合物的最终浓度为5 μ M，以接近口服泛醌治疗患者的CoQ（10）血浆浓度。补充CoQ（10）一周但不补充24小时使CoQ（10）缺陷的成纤维细胞中的ATP水平和ATP/ADP比率加倍，使细胞的生物能量学状态正常化。其他化合物不影响细胞生物能量学。结论/意义：这些结果表明：1）辅酶Q（10）到达线粒体呼吸链的药代动力学延迟; 2）在辅酶Q（10）缺乏的条件下，短尾泛醌类似物不能在线粒体呼吸链中取代辅酶Q（10）;和3）氧化应激和细胞死亡可以通过施用亲脂性或亲水性抗氧化剂来抵消。我们的体外实验结果表明，原发性辅酶Q（10）缺乏症应通过辅酶Q（10）补充剂治疗，而不是短尾泛醌类似物，如艾地苯醌或辅酶Q（2）。如果存在氧化应激，应考虑补充使用生物利用度高的抗氧化剂。
Background: Coenzyme Q(10) (CoQ(10)) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress.Methodology/Principal Findings: To test these concepts, we have evaluated the effects of CoQ(10), coenzyme Q(2) (CoQ(2)), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ(10) deficiency. A final concentration of 5 mu M of each compound was chosen to approximate the plasma concentration of CoQ(10) of patients treated with oral ubiquinone. CoQ(10) supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ(10) deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements.Conclusions/Significance: These results indicate that: 1) pharmacokinetics of CoQ(10) in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ(10) in the mitochondrial respiratory chain under conditions of CoQ(10) deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ(10) deficiencies should be treated with CoQ(10) supplementation but not with short-tail ubiquinone analogs, such as idebenone or CoQ(2). Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.