Department of Medicine (S.Z., Z.C., M.Z., S.S., C.T., Y.G., A.N., W.F., S.M.E., X.F.), University of California, San Diego, La Jolla.
Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, China (S.Z., Z.C., O.K.).
Circ Heart Fail. 2021 Jun;14(6):e008289. doi: 10.1161/CIRCHEARTFAILURE.121.008289. Epub 2021 Jun 15.
Cardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in (), encoding a mitochondrial acyltransferase required for cardiolipin remodeling. Despite recent description of a mouse model of BTHS cardiomyopathy, an in-depth analysis of specific lipid abnormalities and mitochondrial form and function in an in vivo BTHS cardiomyopathy model is lacking.
We performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group).
cardiomyocyte-specific knockout mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cardiomyocyte-specific knockout mice exhibited lethality before 2 months of age, with significantly enlarged hearts. More than 80% of cardiomyocyte-specific knockout displayed ventricular dilation at 16 weeks of age and survived until 50 weeks of age. Full parameter analysis of cardiac cardiolipin profiles demonstrated lower total cardiolipin concentration, abnormal cardiolipin fatty acyl composition, and elevated monolysocardiolipin to cardiolipin ratios in Taz cardiomyocyte-specific knockout, relative to controls. Mitochondrial contact site and cristae organizing system and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired. In keeping with observed mitochondrial abnormalities, seahorse experiments demonstrated impaired mitochondrial respiration capacity.
Our mouse model mirrors multiple physiological and biochemical aspects of BTHS cardiomyopathy. Our results give important insights into the underlying cause of BTHS cardiomyopathy and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, or other mitochondrial-related cardiomyopathies.
心肌病是 Barth 综合征（BTHS）的主要临床特征，BTHS 是一种 X 连锁的线粒体脂质紊乱，由编码线粒体酰基转移酶的基因突变引起，该酶对于心磷脂重塑是必需的。尽管最近描述了 BTHS 心肌病的小鼠模型，但在体内 BTHS 心肌病模型中，缺乏对特定脂质异常和线粒体形态及功能的深入分析。
我们对新生成的肌球蛋白特异性敲除小鼠和 Cre 阴性对照小鼠（每组 n≥3）的心脏功能、心磷脂种类谱以及线粒体结构和功能进行了深入评估。
肌球蛋白特异性敲除小鼠重现了 BTHS 和线粒体心肌病的典型特征。少于 5%的肌球蛋白特异性敲除小鼠在 2 个月前发生致死性，心脏明显增大。超过 80%的肌球蛋白特异性敲除小鼠在 16 周龄时出现心室扩张，并存活至 50 周龄。对心脏心磷脂谱的全面参数分析表明，相对于对照组，Taz 肌球蛋白特异性敲除小鼠的心磷脂总浓度降低，心磷脂脂肪酸组成异常，单心磷脂酰甘油与心磷脂的比值升高。线粒体接触点和嵴组织系统以及 F1F0-ATP 合酶复合物，这些对于嵴形态发生是必需的，在肌球蛋白特异性敲除中是异常的，导致洋葱形线粒体。高分子量呼吸链超复合物的组织也受损。与观察到的线粒体异常一致， Seahorse 实验表明线粒体呼吸能力受损。
我们的小鼠模型反映了 BTHS 心肌病的多个生理和生化方面。我们的结果深入了解了 BTHS 心肌病的潜在原因，并为测试治疗 BTHS 心肌病或其他与线粒体相关的心肌病的方法提供了框架。
