Proteomic investigation of cultivated fibroblasts from patients with mitochondrial short-chain acyl-CoA dehydrogenase deficiency
Proteomic investigation of cultivated fibroblasts from patients with mitochondrial short-chain acyl-CoA dehydrogenase deficiency
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DOI：
10.1016/j.ymgme.2014.01.007
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发表时间：
2014-03-01
影响因子：
3.8
通讯作者：
Palmfeldt, Johan
中科院分区：
文献类型：
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作者：
Edhager, Anders V.;Stenbroen, Vibeke;Palmfeldt, Johan
短链酰辅酶A脱氢酶(SCAD)缺乏症是一种罕见的常染色体隐性遗传性疾病，其发病机制尚未明确。在本研究中，在一项大规模的蛋白质组学研究中，研究了5名SCAD基因Acads错义变异纯合子患者的线粒体蛋白质组，以定位与该病相关的蛋白质扰动。研究了Acads中c.319C>；T/p.Arg107 Cys(n=2)或c.1138C>；T/p.Arg380Trp(n=3)纯合子患者细胞的成纤维细胞培养。利用高精度纳液色谱串联质谱(NanoLC-MS/MS)对来源于这些培养物的线粒体蛋白质组进行了无标记蛋白质组学分析，鉴定和定量了300多个线粒体蛋白质。在ACADS患者中，与对照组相比，携带C.319C>变异的患者中有13种蛋白质水平发生了显著变化，它们属于不同的途径，如抗氧化系统和氨基酸代谢。在携带C.1138C>；T变异的患者中，发现22种蛋白质发生显著改变，其中包括与脂肪酸β氧化、氨基酸代谢和蛋白质质量控制系统相关的蛋白质。在两组患者中都发现了三种蛋白的显著调控：腺苷酸激酶4(AK4)、核苷二磷酸激酶A(NME1)和乙醛脱氢酶家族4成员A1(ALDH4A1)。蛋白AK4和NME1值得进一步研究，因为它们参与了能量重新编程、细胞生存和增殖，并与SCAD缺陷和相关的代谢紊乱有关。(C)2014 Elsevier Inc.保留所有权利。
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a rare inherited autosomal recessive disorder with not yet well established mechanisms of disease. In the present study, the mitochondrial proteome of five symptomatic patients homozygous for missense variations in the SCAD gene ACADS was investigated in an extensive large-scale proteomic study to map protein perturbations linked to the disease.Fibroblast cultures of patient cells homozygous for either c.319C>T/p.Arg107Cys (n = 2) or c.1138C>T/p.Arg380Trp (n = 3) in ACADS, and healthy controls (normal human dermal fibroblasts), were studied. The mitochondrial proteome derived from these cultures was analyzed by label free proteomics using high mass accuracy nanoliquid chromatography tandem mass spectrometry (nanoLC-MS/MS).More than 300 mitochondrial proteins were identified and quantified. Thirteen proteins had significant alteration in protein levels in patients carrying variation c.319C>T in ACADS compared to controls and they belonged to various pathways, such as the antioxidant system and amino acid metabolism. Twenty-two proteins were found significantly altered in patients carrying variation c.1138C>T which included proteins associated with fatty acid beta-oxidation, amino acid metabolism and protein quality control system. Three proteins were found significantly regulated in both patient groups: adenylate kinase 4 (AK4), nucleoside diphosphate kinase A (NME1) and aldehyde dehydrogenase family 4 member Al (ALDH4A1). Proteins AK4 and NME1 deserve further investigation because of their involvement in energy reprogramming, cell survival and proliferation with relevance for SCAD deficiency and related metabolic disorders. (C) 2014 Elsevier Inc. All rights reserved.