Subcomplex Ilambda specifically controls integrated mitochondrial functions in Caenorhabditis elegans.
Subcomplex Ilambda specifically controls integrated mitochondrial functions in Caenorhabditis elegans.
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DOI：
10.1371/journal.pone.0006607
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发表时间：
2009-08-12
期刊：
影响因子：
3.7
通讯作者：
Sedensky MM
中科院分区：
文献类型：
--
作者：
Falk MJ;Rosenjack JR;Polyak E;Suthammarak W;Chen Z;Morgan PG;Sedensky MM
复合物I功能障碍是人类线粒体疾病的常见异质性原因，其发病机制知之甚少。人类和秀丽隐杆线虫之间的复合物I组成的广泛保守允许在整个动物和线粒体水平上分析单个亚基对线粒体功能的贡献。我们提供了第一个实验验证编译复杂的I组成的C。elegans，证明与人类复合物I具有84%的保守性。在C.通过RNA干扰产生的敲低编码28个复合物I结构亚基和2个组装因子的核基因，并非所有复合物I亚基都直接影响呼吸能力。沿着电子传递途径的亚复合物Iλ亚基沿着特异性地控制整个动物的麻醉敏感性和复合物II的上调，与它们对复合物I依赖性氧化能力的相对损害成比例。复杂I功能障碍的翻译分析促进了对线粒体疾病个体基因贡献的机制理解。我们表明，复合物I缺陷的功能后果不同的特定亚基是有缺陷的。
Complex I dysfunction is a common, heterogeneous cause of human mitochondrial disease having poorly understood pathogenesis. The extensive conservation of complex I composition between humans and Caenorhabditis elegans permits analysis of individual subunit contribution to mitochondrial functions at both the whole animal and mitochondrial levels. We provide the first experimentally-verified compilation of complex I composition in C. elegans, demonstrating 84% conservation with human complex I. Individual subunit contribution to mitochondrial respiratory capacity, holocomplex I assembly, and animal anesthetic behavior was studied in C. elegans by RNA interference-generated knockdown of nuclear genes encoding 28 complex I structural subunits and 2 assembly factors. Not all complex I subunits directly impact respiratory capacity. Subcomplex Iλ subunits along the electron transfer pathway specifically control whole animal anesthetic sensitivity and complex II upregulation, proportionate to their relative impairment of complex I-dependent oxidative capacity. Translational analysis of complex I dysfunction facilitates mechanistic understanding of individual gene contribution to mitochondrial disease. We demonstrate that functional consequences of complex I deficiency vary with the particular subunit that is defective.