Deficiency of the transacylase tafazzin due to loss of function variants in the X-chromosomal TAFAZZIN gene causes Barth syndrome (BTHS) with severe neonatal or infantile cardiomyopathy, neutropenia, myopathy, and short stature. The condition is characterized by drastic changes in the composition of cardiolipins, a mitochondria-specific class of phospholipids. Studies examining the impact of tafazzin deficiency on the metabolism of other phospholipids have so far generated inhomogeneous and partly conflicting results. Recent studies showed that the cardiolipin composition in cells and different murine tissues is highly dependent on the surrounding lipid environment. In order to study the relevance of different lipid states and tafazzin function for cardiolipin and phospholipid homeostasis we conducted systematic modulation experiments in a CRISPR/Cas9 knock-out model for BTHS. We found that—irrespective of tafazzin function—the composition of cardiolipins strongly depends on the nutritionally available lipid pool. Tafazzin deficiency causes a consistent shift towards cardiolipin species with more saturated and shorter acyl chains. Interestingly, the typical biochemical BTHS phenotype in phospholipid profiles of HEK 293T TAZ knock-out cells strongly depends on the cellular lipid context. In response to altered nutritional lipid compositions, we measured more pronounced changes on phospholipids that were largely masked under standard cell culturing conditions, therewith giving a possible explanation for the conflicting results reported so far on BTHS lipid phenotypes.

中文翻译：

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脂质环境调节野生型和 tafazzin 缺陷细胞的心磷脂和磷脂构成

由于 X 染色体TAFAZZIN的功能变体丧失导致转酰基酶 tafazzin 缺乏基因导致 Barth 综合征 (BTHS) 伴有严重的新生儿或婴儿心肌病、中性粒细胞减少症、肌病和身材矮小。这种情况的特点是心磷脂（一种线粒体特异性磷脂）的组成发生了剧烈变化。迄今为止，关于 tafazzin 缺乏对其他磷脂代谢影响的研究产生了不均匀且部分相互矛盾的结果。最近的研究表明，细胞和不同小鼠组织中的心磷脂成分高度依赖于周围的脂质环境。为了研究不同脂质状态和 tafazzin 功能与心磷脂和磷脂稳态的相关性，我们在 BTHS 的 CRISPR/Cas9 敲除模型中进行了系统调节实验。我们发现——不管 tafazzin 的功能如何——心磷脂的组成在很大程度上取决于营养可用的脂质池。Tafazzin 缺乏导致向心磷脂种类的持续转变，其具有更饱和和更短的酰基链。有趣的是，HEK 293T 磷脂谱中典型的生化 BTHS 表型TAZ敲除细胞强烈依赖于细胞脂质环境。为了响应营养脂质成分的改变，我们测量了在标准细胞培养条件下大部分被掩盖的磷脂的更明显变化，从而为迄今为止报告的关于 BTHS 脂质表型的相互矛盾的结果提供了可能的解释。