Barth syndrome (BTHS) is an X-linked recessive multisystem disorder caused by mutations in the TAZ gene (TAZ, G 4.5, OMIM 300394) that encodes for the acyltransferase tafazzin. This protein is highly expressed in the heart and plays a significant role in cardiolipin biosynthesis. Heart disease is the major clinical manifestation of BTHS with a high incidence in early life. Although the genetic basis of BTHS and tetralinoleoyl cardiolipin deficiency in BTHS-affected individuals are well-established, downstream metabolic changes in cardiac metabolism are still uncovered. Our study aimed to characterize TAZ-induced metabolic perturbations in the heart. Control (PGP1-TAZWT) and TAZ mutant (PGP1-TAZ517delG) iPS-CM were incubated with 13C6-glucose and 13C5-glutamine and incorporation of 13C into downstream Krebs cycle intermediates was traced. Our data reveal that TAZ517delG induces accumulation of cellular long chain acylcarnitines and overexpression of fatty acid binding protein (FABP4). We also demonstrate that TAZ517delG induces metabolic alterations in pathways related to energy production as reflected by high glucose uptake, an increase in glycolytic lactate production and a decrease in palmitate uptake. Moreover, despite mitochondrial dysfunction, in the absence of glucose and fatty acids, TAZ517delG-iPS-CM can use glutamine as a carbon source to replenish the Krebs cycle.

中文翻译：

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Barth综合征：用诱导的多能干细胞衍生的心肌细胞探索心脏代谢。

Barth综合征（BTHS）是X连锁隐性多系统疾病，由TAZ基因（TAZ，G 4.5，OMIM 300394）中的突变引起，该突变编码酰基转移酶他法津。该蛋白在心脏中高表达，在心磷脂的生物合成中起重要作用。心脏病是BTHS的主要临床表现，在生命的早期阶段发病率很高。尽管在受BTHS影响的个体中BTHS和四亚油酰基心磷脂缺乏症的遗传基础已经建立，但仍未发现心脏代谢中的下游代谢变化。我们的研究旨在表征TAZ引起的心脏代谢紊乱。将对照（PGP1-TAZWT）和TAZ突变体（PGP1-TAZ517delG）iPS-CM与13C6-葡萄糖和13C5-谷氨酰胺孵育，并追踪13C向下游Krebs循环中间体的掺入。我们的数据表明TAZ517delG诱导细胞长链酰基肉碱的积累和脂肪酸结合蛋白（FABP4）的过度表达。我们还证明，TAZ517delG诱导与能量产生相关的途径中的代谢改变，这反映为高葡萄糖摄取，糖酵解乳酸盐产生的增加和棕榈酸酯摄取的减少。此外，尽管线粒体功能障碍，但在缺少葡萄糖和脂肪酸的情况下，TAZ517delG-iPS-CM可以使用谷氨酰胺作为碳源来补充克雷布斯循环。糖酵解乳酸盐产量的增加和棕榈酸酯摄取的减少。此外，尽管线粒体功能障碍，但在缺少葡萄糖和脂肪酸的情况下，TAZ517delG-iPS-CM可以使用谷氨酰胺作为碳源来补充克雷布斯循环。糖酵解乳酸盐产量的增加和棕榈酸酯摄取的减少。此外，尽管线粒体功能障碍，但在缺少葡萄糖和脂肪酸的情况下，TAZ517delG-iPS-CM可以使用谷氨酰胺作为碳源来补充克雷布斯循环。