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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Functional alteration of cytochrome c oxidase by SURF1 mutations in Leigh syndrome
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Functional alteration of cytochrome c oxidase by SURF1 mutations in Leigh syndrome

机译：Leigh综合征中SURF1突变对细胞色素c氧化酶的功能改变

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Subacute necrotising encephalomyopathy (Leigh syndrome) due to cytochrome c oxidase (COX) deficiency is often caused by mutations in the SURF1 gene, encoding the Surf1 protein essential for COX assembly. We have investigated five patients with different SURF1 mutations resulting in the absence of Surf1 protein. All of them presented with severe and generalised COX defect. Immunoelectrophoretic analysis of cultured fibroblasts revealed 85% decrease of the normal-size COX complexes and significant accumulation of incomplete COX assemblies of 90-120 kDa. Spectrophotometric assay of COX activity showed a 70-90% decrease in lauryl maltoside (LM)-solubilised fibroblasts. In contrast, oxygen consumption analysis in whole cells revealed only a 13-31% decrease of COX activity, which was completely inhibited by detergent in patient cells but not in controls. In patient fibroblasts ADP-stimulated respiration was 50% decreased and cytofluorometry showed a significant decrease of mitochondrial membrane potential ΔΨ_m in state 4, as well as a 2.4-fold higher sensitivity of ΔΨ_m to uncoupler. We conclude that the absence of the Surf1 protein leads to the formation of incomplete COX complexes, which in situ maintain rather high electron-transport activity, while their H~+-pumping is impaired. Enzyme inactivation by the detergent in patient cells indicates instability of incomplete COX assemblies.
机译：由于细胞色素C氧化酶（COX）缺乏而引起的亚急性坏死性脑病（Leigh综合征）通常是由SURF1基因的突变引起的，该基因编码了COX组装所必需的Surf1蛋白。我们调查了五名患者，这些患者具有不同的SURF1突变，导致没有Surf1蛋白。他们都表现出严重而广泛的COX缺陷。培养的成纤维细胞的免疫电泳分析表明，正常大小的COX复合物减少了85％，并且90-120 kDa的不完整COX组件大量积聚。分光光度法测定COX活性表明，月桂基麦芽糖苷（LM）溶解的成纤维细胞减少了70-90％。相比之下，全细胞耗氧分析显示，COX活性仅降低了13-31％，这在患者细胞中被去污剂完全抑制了，但在对照中却没有。在患者成纤维细胞中，ADP刺激的呼吸下降了50％，细胞荧光检测显示状态4的线粒体膜电位ΔΨ_m显着降低，并且ΔΨ_m对解偶联剂的敏感性提高了2.4倍。我们得出的结论是，Surf1蛋白的缺失会导致形成不完整的COX复合物，该复合物原位维持相当高的电子传输活性，而其H +泵浦则受到损害。清洁剂在患者细胞中使酶失活表明不完整的COX组件不稳定。

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