Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy.
Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy.
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心磷脂重塑缺陷损害Barth综合征心肌病小鼠模型的线粒体结构和功能。
DOI：
10.1161/circheartfailure.121.008289
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Fang X
中科院分区：
文献类型：
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作者：
Zhu S;Chen Z;Zhu M;Shen Y;Leon LJ;Chi L;Spinozzi S;Tan C;Gu Y;Nguyen A;Zhou Y;Feng W;Vaz FM;Wang X;Gustafsson AB;Evans SM;Kunfu O;Fang X
心肌病是Barth综合征（BTHS）的主要临床特征，BTHS是一种x连锁线粒体脂质疾病，由他法津（TAZ）突变引起，他法津编码心磷脂（CL）重塑所需的线粒体酰基转移酶。尽管最近描述了BTHS心肌病的小鼠模型，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。我们对新生成的Taz心肌细胞特异性敲除（cKO）小鼠和Cre阴性对照小鼠（每组n≥3只）的心功能、CL物种谱、线粒体结构和功能进行了深入评估。Taz cKO小鼠再现了BTHS和线粒体心肌病的典型特征。不到5%的cKO小鼠在2个月前表现出致命性，心脏明显增大。81.8%的cKOs在16周龄时出现心室扩张，并存活至50周龄。心脏CL谱的全参数分析显示，与对照组相比，Taz cKO患者的总CL浓度较低，CL脂肪酰基组成异常，MLCL / CL比值升高。嵴形态发生所需的MICOS和F1F0-ATP合成酶复合物异常，导致“洋葱形”线粒体。高分子量呼吸链超配合物的组织也受到损害。与观察到的线粒体异常相一致，海马实验表明线粒体呼吸能力受损。我们的小鼠模型反映了BTHS心肌病的多个生理生化方面。我们的研究结果为BTHS心肌病的潜在病因提供了重要的见解，并为BTHS心肌病和/或其他线粒体相关心肌病的治疗方法测试提供了框架。
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 (CL) 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 are lacking. We performed in depth assessment of cardiac function, CL species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout (cKO) mice and Cre negative control mice (n≥3 per group). Taz cKO mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cKO mice exhibited lethality prior to 2 months of age, with significantly enlarged hearts. 81.8% of cKOs displayed ventricular dilation at 16-weeks of age, and survived until 50-weeks of age. Full parameter analysis of cardiac CL profiles demonstrated lower total CL concentration, abnormal CL fatty acyl composition, and elevated MLCL to CL ratios in Taz cKO, relative to controls. MICOS 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 etiology of BTHS cardiomyopathy, and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, and/or other mitochondrial-related cardiomyopathies.