Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis
Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis
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DOI：
10.1093/hmg/ddh027
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发表时间：
2004-02-01
影响因子：
3.5
通讯作者：
Lemire, BD
中科院分区：
文献类型：
--
作者：
Grad, LI;Lemire, BD
线粒体功能障碍，估计发病率为1/10 000活产，是最常见的遗传决定的条件之一。编码NADH-泛醌氧化还原酶或复合物I的51 kDa活性位点亚基的人NDUFV 1基因中的错义突变可导致严重的神经系统疾病。由于线粒体疾病的罕见性和经常散发性，大多数突变的发病机制仍然知之甚少。我们已经产生了秀丽隐杆线虫的转基因株，其表达nuo-1基因中的致病突变，NDUFV 1基因的同源物。转基因菌株表现出复合物I功能障碍的标志性特征，如乳酸酸中毒和NADH依赖性线粒体呼吸降低。它们对外源性氧化应激也高度敏感，这表明细胞对活性氧的防御机制已经受到内源性应激的影响。由NDUFV 1突变引起的乳酸酸中毒可以用维生素核黄素和硫胺素或二氯乙酸钠（丙酮酸脱氢酶复合物的激活剂）部分纠正，从而显著增加动物适应性。令人惊讶的是，细胞色素c氧化酶活性和蛋白质水平降低，建立了复合物I和IV之间的连接。我们的研究结果表明，复合物I突变以多种方式发挥其致病作用：通过阻碍NADH的代谢，通过增加活性氧的产生，以及通过干扰其他线粒体呼吸链组分的功能或组装。
Mitochondrial dysfunction, with an estimated incidence of 1 in 10 000 live births, is among the most common genetically determined conditions. Missense mutations in the human NDUFV1 gene, which encodes the 51 kDa active site subunit of the NADH-ubiquinone oxidoreductase or complex I, can lead to severe neurological disorders. Owing to the rare and often sporadic nature of mitochondrial disorders, the mechanisms of pathogenesis of most mutations remain poorly understood. We have generated transgenic strains of Caenorhabditis elegans that express disease-causing mutations in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrate hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration. They are also hypersensitive to exogenous oxidative stress, suggesting that cellular defense mechanisms against reactive oxygen species are already taxed by an endogenous stress. The lactic acidosis induced by the NDUFV1 mutations could be partially corrected with the vitamins riboflavin and thiamine or with sodium dichloroacetate, an activator of the pyruvate dehydrogenase complex, resulting in significant increases in animal fitness. Surprisingly, cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Our results indicate that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.