Mitochondrial complex I function modulates volatile anesthetic sensitivity in C-elegans
Mitochondrial complex I function modulates volatile anesthetic sensitivity in C-elegans
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DOI：
10.1016/j.cub.2006.06.072
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发表时间：
2006-08-22
期刊：
影响因子：
9.2
通讯作者：
Sedensky, Margaret M.
中科院分区：
文献类型：
--
作者：
Falk, Marni J.;Kayser, Ernst-Bernhard;Sedensky, Margaret M.
尽管挥发性麻醉剂在临床上广泛使用，但其作用机制仍不清楚[1-6]。对线虫C. elegrans对挥发性麻醉剂敏感性改变的动物的研究鉴定了线粒体复合物I的核编码亚基中的突变体[7，8]。这提出了一个问题，即线粒体功能障碍是否可能是挥发性麻醉剂发挥作用的主要机制，而不是不利的次要作用[9，10]。我们在这里报告分析额外的C。在人类基因的直向同源物中，线虫突变有助于形成复合物I、复合物II、复合物III和辅酶Q [11-14]。为了进一步表征复合物I的特殊贡献，我们生成了四个亚纯C。线虫突变体编码不同的复合物I亚基[15]。我们的主要发现是确定了复合碘依赖性氧化磷酸化能力与挥发性麻醉剂敏感性之间的明确相关性。这些扩展数据将易处理动物模型中麻醉作用的生理决定因素与线粒体肌病儿童中的类似临床观察结果联系起来[16]。这项工作是第一个具体牵连复杂的I依赖性氧化磷酸化功能作为挥发性麻醉效果的主要介质。
Despite the widespread clinical use of volatile anesthetics, their mechanisms of action remain unknown [1-6]. An unbiased genetic screen in the nematode C. elegrans for animals with altered volatile anesthetic sensitivity identified a mutant in a nuclear-encoded subunit of mitochondrial complex I [7, 8]. This raised the question of whether mitochondrial dysfunction might be the primary mechanism by which volatile anesthetics act, rather than an untoward secondary effect [9, 10]. We report here analysis of additional C. elegans mutations in orthologs of human genes that contribute to the formation of complex I, complex II, complex III, and coenzyme Q [11-14]. To further characterize the specific contribution of complex I, we generated four hypomorphic C. elegans mutants encoding different complex I subunits [15]. Our main finding is the identification of a clear correlation between complex I-dependent oxidative phosphorylation capacity and volatile anesthetic sensitivity. These extended data link a physiologic determinant of anesthetic action in a tractable animal model to similar clinical observations in children with mitochondrial myopathies [16]. This work is the first to specifically implicate complex I-dependent oxidative phosphorylation function as a primary mediator of volatile anesthetic effect.