Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome
Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome
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DOI：
10.1016/j.scr.2013.05.005
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发表时间：
2013-09-01
影响因子：
1.2
通讯作者：
Guan, Kaomei
中科院分区：
文献类型：
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作者：
Dudek, Jan;Cheng, I-Fen;Guan, Kaomei
巴特综合征（BTHS）患者在Tafazzin（TAZ1）中携带突变的患者参与了心霉素的最终成熟，并表现出扩张的心肌病，骨骼肌病，生长延迟和中性粒细胞减少。为了研究BTHS患者的线粒体功能如何受损，我们产生了诱导的多能干细胞（IPSC），以开发出一种新型且相关的BTHS模型系统。 BTHS-IPSC由三名具有不同突变患者的皮肤成纤维细胞产生，在TAZ1表达的多能标记物中，能够分化为从体外和体内所有三个细菌层的细胞中分化。我们使用这些细胞来研究tafazzin缺乏对线粒体的影响（氧化磷酸化。我们发现心氨基脂蛋白的重塑受损，基础氧气消耗率和BTHS-IPSCS的最大呼吸量的同时测量。酸化率使我们对BTHS患者的代谢缺陷进行了彻底的评估凝胶分析表明，呼吸下降与呼吸链超复合物的急剧结构变化相吻合，导致反应性氧的产生大量增加，我们的数据表明BTHS-IPSC能够通过重新培养疾病表型来对BTH进行建模，从而成为重要的BTH。研究疾病机制（C）。
Barth syndrome (BTHS) patients carrying mutations in tafazzin (TAZ1), which is involved in the final maturation of cardiolipin, present with dilated cardiomyopathy, skeletal myopathy, growth retardation and neutropenia. To study how mitochondrial function is impaired in BTHS patients, we generated induced pluripotent stem cells (iPSCs) to develop a novel and relevant human model system for BTHS. BTHS-iPSCs generated from dermal fibroblasts of three patients with different mutations in TAZ1 expressed pluripotency markers, and were able to differentiate into cells derived from all three germ layers both in vitro and in vivo. We used these cells to study the impact of tafazzin deficiency on mitochondria( oxidative phosphorylation. We found an impaired remodeling of cardiolipin, a dramatic decrease in basal oxygen consumption rate and in the maximal respiratory capacity in BTHS-iPSCs. Simultaneous measurement of extra-cellular acidification rate allowed us a thorough assessment of the metabolic deficiency in BTHS patients. Blue native gel analyses revealed that decreased respiration coincided with dramatic structural changes in respiratory chain supercomplexes leading to a massive increase in generation of reactive oxygen species. Our data demonstrate that BTHS-iPSCs are capable of modeling BTHS by recapitulating the disease phenotype and thus are important tools for studying the disease mechanism. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.