Theunissen Tom E J, Gerards Mike, Hellebrekers Debby M E I, van Tienen Florence H, Kamps Rick, Sallevelt Suzanne C E H, Hartog Elvira N M M-D, Scholte Hans R, Verdijk Robert M, Schoonderwoerd Kees, de Coo Irenaeus F M, Szklarczyk Radek, Smeets Hubert J M
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands.
Department of Genetics and Cell Biology, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands.
Front Mol Neurosci. 2017 Oct 18;10:336. doi: 10.3389/fnmol.2017.00336. eCollection 2017.
Mitochondrial disorders are genetically and clinically heterogeneous, mainly affecting high energy-demanding organs due to impaired oxidative phosphorylation (OXPHOS). Currently, effective treatments for OXPHOS defects, with complex I deficiency being the most prevalent, are not available. Yet, clinical practice has shown that some complex I deficient patients benefit from a high-fat or ketogenic diet, but it is unclear how these therapeutic diets influence mitochondrial function and more importantly, which complex I patients could benefit from such treatment. Dietary studies in a complex I deficient patient with exercise intolerance showed increased muscle endurance on a high-fat diet compared to a high-carbohydrate diet. We performed whole-exome sequencing to characterize the genetic defect. A pathogenic homozygous p.G212V missense mutation was identified in the gene, encoding an early assembly factor of complex I. A complementation study in fibroblasts confirmed that the p.G212V mutation caused the complex I deficiency. The mechanism turned out to be an incomplete assembly of the peripheral arm of complex I, leading to a decrease in the amount of mature complex I. The patient clinically improved on a high-fat diet, which was supported by the 25% increase in maximal OXPHOS capacity in TMEM126B defective fibroblast by the saturated fatty acid palmitic acid, whereas oleic acid did not have any effect in those fibroblasts. Fibroblasts of other patients with a characterized complex I gene defect were tested in the same way. Patient fibroblasts with complex I defects in NDUFS7 and NDUFAF5 responded to palmitic acid, whereas ACAD9, NDUFA12, and NDUFV2 defects were non-responding. Although the data are too limited to draw a definite conclusion on the mechanism, there is a tendency that protein defects involved in early assembly complexes, improve with palmitic acid, whereas proteins defects involved in late assembly, do not. Our data show at a clinical and biochemical level that a high fat diet can be beneficial for complex I patients and that our cell line assay will be an easy tool for the selection of patients, who might potentially benefit from this therapeutic diet.
线粒体疾病在遗传和临床上具有异质性，主要由于氧化磷酸化（OXPHOS）受损而影响高能量需求器官。目前，对于OXPHOS缺陷尚无有效的治疗方法，其中复合物I缺乏最为普遍。然而，临床实践表明，一些复合物I缺乏的患者从高脂或生酮饮食中获益，但尚不清楚这些治疗性饮食如何影响线粒体功能，更重要的是，哪些复合物I缺乏的患者可以从这种治疗中获益。一项针对一名运动不耐受的复合物I缺乏患者的饮食研究表明，与高碳水化合物饮食相比，高脂饮食可提高肌肉耐力。我们进行了全外显子组测序以确定遗传缺陷。在编码复合物I早期组装因子的基因中鉴定出一个致病性纯合p.G212V错义突变。在成纤维细胞中进行的互补研究证实，p.G212V突变导致复合物I缺乏。结果表明，其机制是复合物I外周臂组装不完全，导致成熟复合物I的数量减少。该患者在高脂饮食后临床症状改善，饱和脂肪酸棕榈酸使TMEM126B缺陷成纤维细胞的最大OXPHOS能力增加25%，而油酸对这些成纤维细胞没有任何影响，这支持了上述结论。以同样的方式对其他具有特征性复合物I基因缺陷的患者的成纤维细胞进行了测试。在NDUFS7和NDUFAF5中存在复合物I缺陷的患者成纤维细胞对棕榈酸有反应，而ACAD9、NDUFA12和NDUFV2缺陷则无反应。尽管数据有限，无法就机制得出明确结论，但存在一种趋势，即参与早期组装复合物的蛋白质缺陷可通过棕榈酸得到改善，而参与晚期组装的蛋白质缺陷则不能。我们的数据在临床和生化水平上表明，高脂饮食对复合物I缺乏的患者可能有益，并且我们的细胞系检测将成为选择可能从这种治疗性饮食中获益的患者的简便工具。
