Barth syndrome (BTHS) is an X-linked genetic condition caused by defects in TAZ, which encodes a transacylase involved in the remodeling of the inner mitochondrial membrane phospholipid, cardiolipin (CL). As such, CL has been implicated in numerous mitochondrial functions, and the role of defective CL in the clinical pathology of BTHS is under intense investigation. We used untargeted proteomics, shotgun lipidomics, gene expression analysis, and targeted metabolomics to identify novel areas of mitochondrial dysfunction in a new model of TAZ deficiency in HEK293 cells. Functional annotation analysis of proteomics data revealed abnormal regulation of mitochondrial respiratory chain complex I (CI), driven by the reduced abundance of 6 CI associated proteins in TAZ-deficient HEK293 cells: MT-ND3, NDUFA5, NDUFAB1, NDUFB2, NDUFB4, and NDUFAF1. This resulted in reduced assembly and function of CI in TAZ-deficient HEK293 cells as well as BTHS patient derived lymphoblast cells. We also identified increased abundance of PARL, a rhomboid protein involved in the regulation of mitophagy and apoptosis, and abnormal downstream processing of PGAM5, another mediator of mitochondrial quality control, in TAZ-deficient cells. Lastly, we modulated CL via the phospholipase inhibitor bromoenol lactone and the CL targeted SS-peptide, SS-31, and showed that each is able to remediate abnormalities in CI abundance as well as PGAM5 processing. Thus, mitochondrial respiratory chain CI and PARL/PGAM5 regulated mitochondrial quality control, both of whose functions localize to the inner mitochondrial membrane, are dysregulated due to TAZ deficiency and are partially remediated via modulation of CL.

中文翻译：

---

Barth综合征细胞模型由于心磷脂异常，呼吸链复合体I和线粒体质量控制失调

Barth综合征（BTHS）是由TAZ缺陷引起的X连锁遗传病，它编码参与内部线粒体膜磷脂心磷脂（CL）重塑的转酰基酶。因此，CL已经牵涉到许多线粒体功能，并且有缺陷的CL在BTHS临床病理中的作用正在深入研究中。我们使用非靶向蛋白质组学，shot弹枪脂质组学，基因表达分析和靶向代谢组学来鉴定HEK293细胞中TAZ缺乏症新模型中线粒体功能障碍的新区域。蛋白质组学数据的功能注释分析揭示了线粒体呼吸链复合体I（CI）的异常调节，这是由TAZ缺失的HEK293细胞中6种CI相关蛋白的减少导致的：MT-ND3，NDUFA5，NDUFAB1，NDUFB2，NDUFB4和NDUFAF1 。这导致TAZ缺陷型HEK293细胞以及BTHS患者来源的淋巴母细胞中CI的装配和功能降低。我们还发现，在TAZ缺失的细胞中，PARL（一种参与调节线粒体和细胞凋亡的调节作用的菱形蛋白）和下游异常加工PGAM5（线粒体质量控制的另一种介体）的含量增加。最后，我们通过磷脂酶抑制剂溴烯醇内酯和CL靶向的SS肽SS-31对CL进行了调节，结果表明它们都能修复CI丰度以及PGAM5加工过程中的异常。因此，由于TAZ缺乏，线粒体呼吸链CI和PARL / PGAM5调节的线粒体质量控制均失调，这两种功能均位于TAS缺乏，并且通过CL的调节而部分修复。