Background:Cardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in Tafazzin (TAZ), 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.Methods:We performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group).Results:Taz 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.Conclusions: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.

中文翻译：

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心磷脂重塑缺陷损害巴特综合征心肌病小鼠模型的线粒体结构和功能

背景：心肌病是 Barth 综合征 (BTHS) 的主要临床特征，这是一种由Tafazzin ( TAZ )突变引起的 X 连锁线粒体脂质紊乱，编码心磷脂重塑所需的线粒体酰基转移酶。尽管最近描述了 BTHS 心肌病小鼠模型，但缺乏对体内 BTHS 心肌病模型中特定脂质异常和线粒体形式和功能的深入分析。方法：我们对心脏功能、心磷脂种类概况进行了深入评估，以及我们新生成的Taz心肌细胞特异性敲除小鼠和 Cre 阴性对照小鼠（每组 n≥3）的线粒体结构和功能。结果： Taz心肌细胞特异性敲除小鼠概括了 BTHS 和线粒体心肌病的典型特征。不到 5% 的心肌细胞特异性敲除小鼠在 2 个月大之前表现出致死性，心脏明显增大。超过 80% 的心肌细胞特异性基因敲除在 16 周龄时表现出心室扩张，并存活至 50 周龄。心磷脂概况的全参数分析表明，相对于对照组，Taz 心肌细胞特异性敲除中的心磷脂总浓度较低、心磷脂脂肪酰基组成异常以及单溶心磷脂与心磷脂的比率升高。线粒体接触部位和嵴组织系统以及嵴形态发生所需的 F1F0-ATP 合酶复合物异常，导致形成洋葱形线粒体。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，海马实验证明线粒体呼吸能力受损。结论：我们的小鼠模型反映了 BTHS 心肌病的多个生理和生化方面。我们的结果对 BTHS 心肌病的根本原因提供了重要见解，并为测试 BTHS 心肌病或其他线粒体相关心肌病的治疗方法提供了框架。