Background:Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Because mitochondrial function and ROS formation are regulated by excitation-contraction coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy.Methods:We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca²⁺ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca²⁺ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo.Results:Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca²⁺ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca²⁺ decay through preactivated sarcoplasmic reticulum Ca²⁺-ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca²⁺ uniporter protein that prevented Ca²⁺-induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca²⁺ export through the mitochondrial Na⁺/Ca²⁺ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo.Conclusions:Downregulation of mitochondrial Ca²⁺ uniporter, increased myofilament Ca²⁺ affinity, and preactivated sarcoplasmic reticulum Ca²⁺-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca²⁺ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

中文翻译：

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线粒体 Ca2+ Uniporter 的缺失限制了肌力储备并为 Barth 综合征心肌病的心律失常提供了触发条件和底物

背景：Barth 综合征 (BTHS) 是由编码 tafazzin 的基因突变引起的，该基因催化线粒体心磷脂的成熟，通常在婴儿早期表现为收缩功能障碍。在出生后的最初几个月，BTHS 心肌病通常会转变为一种舒张功能障碍的表型，其射血分数保留、运动期间收缩储备减弱和心律失常易感性。先前的研究将 BTHS 心肌病追溯到活性氧 (ROS) 的线粒体形成。由于线粒体功能和 ROS 形成受兴奋-收缩耦合调节，因此需要综合分析机械-能量耦合来描绘 BTHS 心肌病的发病机制。Taz -KD) 与野生型同窝仔畜相比。在分离的线粒体中测定呼吸链组装和功能、ROS 排放和 Ca ²⁺摄取。兴奋-收缩耦合与线粒体氧化还原状态、ROS 和 Ca ²⁺在分离的、未加载的或预加载的心肌细胞中的摄取相结合，并在体内分析了心脏血流动力学。结果：Taz -KD 小鼠发生心力衰竭，射血分数保留 (>50 %) 和在没有纤维化的情况下舒张功能障碍的年龄依赖性进展。增加的肌丝 Ca ²⁺亲和力和减慢的横桥循环导致舒张功能障碍，部分由加速的舒张 Ca ²⁺补偿通过预活化的肌浆网 Ca ^{2 +} -ATPase衰变。Taz缺乏引起线粒体 Ca ²⁺单向转运蛋白的心脏特异性丢失，该蛋白在 β-肾上腺素能刺激期间阻止 Ca ²⁺诱导的三羧酸循环激活，氧化吡啶核苷酸并引发心肌细胞的心律失常。在体内，Taz- KD 小鼠表现出延长的 QRS 持续时间作为心律失常的底物，并且缺乏对 β-肾上腺素能刺激的正性肌力反应。通过抑制通过线粒体 Na ⁺ /Ca ^{2+ 的}Ca ²⁺输出，可以恢复细胞心律失常和 QRS 波延长，但不会恢复有缺陷的肌力储备交换器。所有改变都发生在体外或体内没有过量线粒体 ROS 的情况下。结论：线粒体 Ca ²⁺单向转运蛋白的下调、肌丝 Ca ²⁺亲和力增加和预激活的肌浆网 Ca ²⁺ -ATPase 引起机械能解偶联，解释舒张期功能障碍和 BTHS 心肌病缺乏正性肌力储备。此外，有缺陷的线粒体 Ca ²⁺摄取提供了室性心律失常的触发因素和底物。这些见解可以指导正在进行的寻找治愈这种孤儿疾病的方法。