Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly
Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly
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DOI：
10.1093/hmg/ddw431
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发表时间：
2017-02-15
影响因子：
3.5
通讯作者：
Riemer, Jan
中科院分区：
文献类型：
--
作者：
Friederich, Marisa W.;Erdogan, Alican J.;Riemer, Jan
一个婴儿提出了致命的婴儿乳酸性酸中毒和心肌病，并被发现有深刻的呼吸链复合物I在肌肉，心脏和肝脏的活动减少。外显子组测序揭示了NDUFB 10中的复合杂合突变，其编码位于复合物I的P-D部分内的辅助亚基。一个突变导致提前终止密码子和缺失蛋白质，而第二个突变用丝氨酸残基取代高度保守的半胱氨酸107。NDUFB 10的蛋白质表达在肌肉和心脏中降低，在肝脏和成纤维细胞中降低较少，导致全酶在830 kDa阶段的扰动组装。NDUFB 10与其他三个复合物I亚基一起被鉴定为膜间空间氧化还原酶CHCHD 4（也称为Mia 40）的底物。我们发现，在其线粒体输入和成熟NDUFB 10瞬时与CHCHD 4相互作用，并获得二硫键。NDUFB 10中半胱氨酸残基107的突变损害了蛋白质的氧化和有效的线粒体积累，并导致非输入前体的降解。我们的研究结果表明，NDUFB 10的突变是与后期组装缺陷相关的复合物I缺陷的新原因，并强调了膜间空间蛋白对复合物I有效组装的作用。
An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the P-D part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.