Gaspard Gerard J, McMaster Christopher R
Departments of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
Departments of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada; Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Chem Phys Lipids. 2015 Dec;193:1-10. doi: 10.1016/j.chemphyslip.2015.09.005. Epub 2015 Sep 26.
Cardiolipin (CL) is a phospholipid with many unique characteristics. CL is synthesized in the mitochondria and resides almost exclusively within the mitochondrial inner membrane. Unlike most phospholipids that have two fatty acyl chains, CL possesses four fatty acyl chains resulting in unique biophysical characteristics that impact several biological processes including membrane fission and fusion. In addition, several proteins directly bind CL including proteins within the electron transport chain, the ADP/ATP carrier, and proteins that mediate mitophagy. Tafazzin is an enzyme that remodels saturated fatty acyl chains within CL to unsaturated fatty acyl chains, loss of function mutations in the TAZ gene encoding tafazzin are causal for the inherited cardiomyopathy Barth syndrome. Cells from Barth syndrome patients as well as several models of Barth have reduced mitochondrial functions including impaired electron transport chain function and increased reactive oxygen species (ROS) production. Mitochondria in cells from Barth syndrome patients, as well as several model organism mimics of Barth syndrome, are large and lack cristae consistent with the recently described role of CL participating in the generation of mitochondrial membrane contact sites. Cells with an inactive TAZ gene have also been shown to have a decreased capacity to undergo mitophagy when faced with stresses such as increased ROS or decreased mitochondrial quality control. This review describes CL metabolism and how defects in CL metabolism cause Barth syndrome, the etiology of Barth syndrome, and known modifiers of Barth syndrome phenotypes some of which could be explored for their amelioration of Barth syndrome in higher organisms.
心磷脂（CL）是一种具有许多独特特性的磷脂。CL在线粒体中合成，几乎仅存在于线粒体内膜中。与大多数具有两条脂肪酰链的磷脂不同，CL拥有四条脂肪酰链，从而产生独特的生物物理特性，影响包括膜裂变和融合在内的多个生物过程。此外，几种蛋白质直接结合CL，包括电子传递链中的蛋白质、ADP/ATP载体以及介导线粒体自噬的蛋白质。塔法辛是一种将CL中的饱和脂肪酰链重塑为不饱和脂肪酰链的酶，编码塔法辛的TAZ基因功能丧失突变是遗传性心肌病巴斯综合征的病因。来自巴斯综合征患者的细胞以及几种巴斯综合征模型的线粒体功能均降低，包括电子传递链功能受损和活性氧（ROS）生成增加。巴斯综合征患者细胞中的线粒体以及几种巴斯综合征的模式生物模拟物中的线粒体都很大且缺乏嵴，这与最近描述的CL参与线粒体膜接触位点生成的作用一致。当面对ROS增加或线粒体质量控制降低等应激时，TAZ基因失活的细胞也被证明线粒体自噬能力下降。这篇综述描述了CL代谢以及CL代谢缺陷如何导致巴斯综合征、巴斯综合征的病因以及已知的巴斯综合征表型修饰因子，其中一些因子可在高等生物中探索其对巴斯综合征的改善作用。
