Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency
Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency
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DOI：
10.1096/fj.07-100149
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发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Hirano, Michio
中科院分区：
文献类型：
--
作者：
Quinzii, Catarina M.;Lopez, Luis C.;Hirano, Michio
辅酶Q（10）（CoQ（10））对线粒体呼吸链中的电子传递和抗氧化防御至关重要。去年，我们报道了辅酶Q（10）生物合成基因的第一个突变，COQ 2，编码4-对羟基苯甲酸：聚异戊二烯转移酶;和PDSS 2，编码decaprenyl二磷酸合酶的亚基2。然而，原发性辅酶Q（10）缺乏症的致病机制尚未得到很好的表征。在这项研究中，我们研究了严重的辅酶Q（10）缺乏对生物能量学，氧化应激和抗氧化防御在培养的皮肤成纤维细胞携带的COQ 2和PDSS 2突变的后果。辅酶Q（10）生物合成途径前两个关键步骤的缺陷会产生不同的生化改变。PDSS 2突变成纤维细胞相对于对照细胞具有12%的辅酶Q（10），并且显著减少ATP合成，但没有显示出增加的活性氧（ROS）产生，氧化应激的迹象或增加的抗氧化防御标志物。相比之下，COQ 2突变成纤维细胞有30%的CoQ（10），ATP合成部分缺陷，以及显著增加的ROS产生和脂质和蛋白质的氧化。在少量细胞系的基础上，我们的结果表明，原发性CoQ（10）缺乏会导致ATP合成和氧化应激的不同缺陷，这可以解释不同的临床特征，并可能导致更合理的治疗策略。
Coenzyme Q(10) (CoQ(10)) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. Last year, we reported the first mutations in CoQ(10) biosynthetic genes, COQ2, which encodes 4-parahydroxybenzoate: polyprenyl transferase; and PDSS2, which encodes subunit 2 of decaprenyl diphosphate synthase. However, the pathogenic mechanisms of primary CoQ(10) deficiency have not been well characterized. In this study, we investigated the consequence of severe CoQ(10) deficiency on bioenergetics, oxidative stress, and antioxidant defenses in cultured skin fibroblasts harboring COQ2 and PDSS2 mutations. Defects in the first two committed steps of the CoQ(10) biosynthetic pathway produce different biochemical alterations. PDSS2 mutant fibroblasts have 12% CoQ(10) relative to control cells and markedly reduced ATP synthesis, but do not show increased reactive oxygen species (ROS) production, signs of oxidative stress, or increased antioxidant defense markers. In contrast, COQ2 mutant fibroblasts have 30% CoQ(10) with partial defect in ATP synthesis, as well as significantly increased ROS production and oxidation of lipids and proteins. On the basis of a small number of cell lines, our results suggest that primary CoQ(10) deficiencies cause variable defects of ATP synthesis and oxidative stress, which may explain the different clinical features and may lead to more rational therapeutic strategies.