Metabolic consequences of a novel missense mutation of the mtDNA CO I gene
Metabolic consequences of a novel missense mutation of the mtDNA CO I gene
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DOI：
10.1093/hmg/11.16.1797
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发表时间：
2002-08-01
影响因子：
3.5
通讯作者：
Kunz, WS
中科院分区：
文献类型：
--
作者：
Varlamov, DA;Kudin, AP;Kunz, WS
我们在1例17岁的持续性部分性癫痫女孩的线粒体DNA(MtDNA)CO I基因编码细胞色素C氧化酶(COX)亚基I中发现了一个新的异质性C6489A错义突变。这种点突变导致高度保守的Leu196到Ileu196的交换。肌肉活检显示单纤维环氧合酶活性降低，环氧合酶抗体结合力降低，说明突变酶的稳定性降低。血液mtDNA分析显示，患者血液中约有30%的突变mtDNA，而两名未患病家庭成员的血液中约有90%的突变mtDNA。定量分析突变基因剂量对单肌纤维水平COX活性的影响，发现一个非常高的阈值-COX缺乏症仅在含有95%突变mtDNA的纤维中观察到。与这种高突变基因剂量阈值明显相反的是，体内对含有类似90%突变mtDNA的指标性患者的皂素通透性肌肉纤维的线粒体功能的研究显示，最大呼吸速率降低，纤维呼吸对氰化物的敏感性增加。这是由于对肌肉纤维呼吸的COX通量控制增加了2倍，COX代谢阈值降低了30%，支持了骨骼肌氧化磷酸化的COX严格控制的概念。
We have identified a novel heteroplasmic C6489A missense mutation in the mitochondrial DNA (mtDNA) CO I gene encoding the cytochrome c oxidase (COX) subunit I in a 17-year-old girl with epilepsia partialis continua. This point mutation leads to an exchange of the highly conserved Leu196 to Ileu196. Muscle biopsy showed in single fibers decreased COX activity and lowered binding of COX antibodies, indicating decreased stability of the mutated enzyme. The analysis of blood mtDNA revealed about 30% mutant mtDNA in the patients blood but about 90% mutant mtDNA in the blood of two non-affected family members. Quantitative analysis of the mutation gene dose effect on COX activity on single muscle fiber level revealed a very high threshold-a COX deficiency was observed only in fibers containing >95% mutant mtDNA. In apparent contrast to this high mutation gene dose threshold, in vivo investigations of mitochondrial function in saponin-permeabilized muscle fibers of the index patient containing similar to90% mutated mtDNA showed decreased maximal rates of respiration and an increased sensitivity of fiber respiration to cyanide. This is due to a 2-fold increase of COX flux control on muscle fiber respiration and a 30% decrease of COX metabolic threshold, supporting the concept of tight COX control of oxidative phosphorylation in skeletal muscle.