Chu I, Chen Ying-Chih, Lai Ruo-Yun, Chan Jui-Fen, Lee Ya-Hui, Balazova Maria, Hsu Yuan-Hao Howard
Department of Chemistry, Tunghai University, Taichung 40704, Taiwan.
Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia.
Membranes (Basel). 2022 Mar 31;12(4):383. doi: 10.3390/membranes12040383.
The pathogenic variant of the gene is directly associated with Barth syndrome. Because tafazzin in the mitochondria is responsible for cardiolipin (CL) remodeling, all molecules related to the metabolism of CL can affect or be affected by mutation. In this study, we intend to recover the distortion of the mitochondrial lipid composition, especially CL, for Barth syndrome treatment. The genetically edited knockout HAP1 cells were demonstrated to be a suitable cellular model, where CL desaturation occurred and monolyso-CL (MLCL) was accumulated. From the species analysis by mass spectrometry, phosphatidylethanolamine showed changed species content after knockout. knockout also caused genetic down-regulation of gene and up-regulation of gene, which may decrease the biosynthesis of CLs and increase the hydrolysis product MLCL. Supplemented phosphatidylglycerol(18:1) (PG(18:1)) was successfully biosynthesized to mature symmetrical CL and drastically decrease the concentration of MLCL to recover the morphology of mitochondria and the cristae shape of inner mitochondria. Newly synthesized mature CL may induce the down-regulation of and genes to potentially decrease MLCL production. The excess supplemented PG was further metabolized into phosphatidylcholine and phosphatidylethanolamine.
该基因的致病变体与巴斯综合征直接相关。由于线粒体中的tafazzin负责心磷脂（CL）重塑，所有与CL代谢相关的分子都会影响或受该突变影响。在本研究中，我们打算恢复线粒体脂质组成的畸变，尤其是CL，用于治疗巴斯综合征。经基因编辑的敲除HAP1细胞被证明是一个合适的细胞模型，其中发生了CL去饱和且单溶血-CL（MLCL）积累。从质谱的物种分析来看，敲除后磷脂酰乙醇胺的物种含量发生了变化。敲除还导致基因的基因下调和基因上调，这可能会减少CL的生物合成并增加水解产物MLCL。补充的磷脂酰甘油（18:1）（PG(18:1)）成功生物合成成熟的对称CL，并大幅降低MLCL浓度，以恢复线粒体形态和线粒体内嵴的形状。新合成的成熟CL可能会诱导和基因下调，从而潜在地减少MLCL的产生。过量补充的PG进一步代谢为磷脂酰胆碱和磷脂酰乙醇胺。
