Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease
Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease
复制标题
DOI：
10.1038/sj.emboj.7601748
复制
发表时间：
2007-07-11
期刊：
影响因子：
11.4
通讯作者：
Ryan, M. T.
中科院分区：
文献类型：
--
作者：
Dunning, C. J. R.;McKenzie, M.;Ryan, M. T.
在人类中，呼吸链的复合体I由7个线粒体DNA(MtDNA)编码的亚基和38个核编码的亚基组成，它们在一个定义不清的过程中组装在一起。到目前为止，只发现了两个复杂的i组装因子，而且每个因子的功能还不清楚。在这里，我们证明了人类复合体I组装因子CIA30(复合体I中间相关蛋白)在组装的早期阶段与新翻译的mtDNA编码的复合体I亚单位结合，然后在后期解离。使用抗体，我们鉴定了一名CIA30缺陷患者，他表现为心脑肌病，复合体I的水平和活性降低。遗传分析显示，该患者编码CIA30的NDUFAF1基因的两个等位基因都发生了突变。患者细胞中的复合体I组装在早期阶段有缺陷，亚基被降解。使用一种新的慢病毒系统，用正常的CIA30来补充患者成纤维细胞的缺陷，恢复了稳定的复合体I水平。我们的结果表明，CIA30是复合体I早期组装的关键组成部分，其基因突变可导致线粒体疾病。
In humans, complex I of the respiratory chain is composed of seven mitochondrial DNA (mtDNA)-encoded and 38 nuclear-encoded subunits that assemble together in a process that is poorly defined. To date, only two complex I assembly factors have been identified and how each functions is not clear. Here, we show that the human complex I assembly factor CIA30 (complex I intermediate associated protein) associates with newly translated mtDNA-encoded complex I subunits at early stages in their assembly before dissociating at a later stage. Using antibodies we identified a CIA30-deficient patient who presented with cardioencephalomyopathy and reduced levels and activity of complex I. Genetic analysis revealed the patient had mutations in both alleles of the NDUFAF1 gene that encodes CIA30. Complex I assembly in patient cells was defective at early stages with subunits being degraded. Complementing the deficiency in patient fibroblasts with normal CIA30 using a novel lentiviral system restored steady-state complex I levels. Our results indicate that CIA30 is a crucial component in the early assembly of complex I and mutations in its gene can cause mitochondrial disease.