The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome.
The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome.
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DOI：
10.1007/s10545-016-9930-4
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发表时间：
2016-05
影响因子：
4.2
通讯作者：
Rahman S
中科院分区：
文献类型：
--
作者：
Kanabus M;Fassone E;Hughes SD;Bilooei SF;Rutherford T;Donnell MO;Heales SJR;Rahman S
生酮饮食(KD)用于治疗包括线粒体疾病在内的遗传性代谢性疾病的兴趣与日俱增。然而，这种饮食可能起作用的机制，以及它是否能使所有患有线粒体疾病的患者受益，目前都不清楚。这项研究集中在参与线粒体生物发生的中链甘油三酯KD的组成部分--癸酸(C10)和核受体PPAR-γ的配基上。应用线粒体呼吸链酶分析、基因表达芯片、定量聚合酶链式反应和流式细胞术，研究了C10对呼吸链复合体I核编码缺陷所致Leigh综合征(LS)患者原代成纤维细胞的作用。在以PPAR-γ介导的方式诊断为LS的成纤维细胞中，C10处理增加了50%的成纤维细胞的柠檬酸合成酶活性，柠檬酸合成酶是细胞线粒体含量的标志。基因表达分析和定量聚合酶链式反应研究表明，C10处理细胞通过增加ACADVL和CPT1的表达，同时下调与葡萄糖代谢相关的基因(PDK3，PDK4)来支持脂肪酸代谢。参与阻止葡萄糖代谢的PCK2和编码过氧化氢酶的CAT表达上调。此外，C10处理也降低了复合体I缺乏(鱼藤酮处理)细胞的氧化应激。然而，由于不是所有LS受试者的细胞似乎都对C10有反应，先前的体外细胞测试可以被用作选择个体进行后续涉及C10制剂的临床研究的一种手段。本文的在线版本(doi：10.1007/s10545-0169930-4)包含补充材料，授权用户可以使用。
There is growing interest in the use of the ketogenic diet (KD) to treat inherited metabolic diseases including mitochondrial disorders. However, neither the mechanism whereby the diet may be working, nor if it could benefit all patients with mitochondrial disease, is known. This study focusses on decanoic acid (C10), a component of the medium chain triglyceride KD, and a ligand for the nuclear receptor PPAR-γ known to be involved in mitochondrial biogenesis. The effects of C10 were investigated in primary fibroblasts from a cohort of patients with Leigh syndrome (LS) caused by nuclear-encoded defects of respiratory chain complex I, using mitochondrial respiratory chain enzyme assays, gene expression microarray, qPCR and flow cytometry. Treatment with C10 increased citrate synthase activity, a marker of cellular mitochondrial content, in 50 % of fibroblasts obtained from individuals diagnosed with LS in a PPAR-γ-mediated manner. Gene expression analysis and qPCR studies suggested that treating cells with C10 supports fatty acid metabolism, through increasing ACADVL and CPT1 expression, whilst downregulating genes involved in glucose metabolism (PDK3, PDK4). PCK2, involved in blocking glucose metabolism, was upregulated, as was CAT, encoding catalase. Moreover, treatment with C10 also decreased oxidative stress in complex I deficient (rotenone treated) cells. However, since not all cells from subjects with LS appeared to respond to C10, prior cellular testing in vitro could be employed as a means for selecting individuals for subsequent clinical studies involving C10 preparations. The online version of this article (doi:10.1007/s10545-016-9930-4) contains supplementary material, which is available to authorized users.