Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.

中文翻译：

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MCU复合物介导的线粒体钙信号在Barth综合征中受损

通过线粒体钙单向转运体 (MCU) 复合物的钙信号可协调线粒体生物能量学与细胞能量需求。新兴研究表明，复合物 MCU 的成孔亚基的稳定性和活性取决于线粒体磷脂心磷脂 (CL)，但这如何影响 Barth 综合征等 CL 缺乏症中钙依赖性线粒体生物能量学。 BTHS）未知。在这里，我们利用了多种 BTHS 模型，包括酵母、小鼠肌肉细胞系以及 BTHS 患者细胞和心脏组织，以表明 CL 是 MCU 复合调节亚基 MICU1 的丰度和稳定性所必需的。有趣的是，BTHS 线粒体中 MICU1 丰度的降低与 MCU 无关。与 MCU 和 MICU1/MICU2 不同，单转运复合体的其他亚基和相关因子，EMRE 和 MCUR1 分别不受 BTHS 模型的影响。与 MICU1 水平的降低一致，我们表明 MICU1 依赖性线粒体钙摄取的动力学受到干扰，并且 BTHS 成肌细胞中线粒体钙信号的急性刺激未能激活丙酮酸脱氢酶，这反过来又会损害还原当量的产生并钝化线粒体生物能学。总之，我们的研究结果表明线粒体钙信号传导的缺陷可能导致在 BTHS 患者中观察到的心脏和骨骼肌病变。我们表明，MICU1 依赖性线粒体钙摄取的动力学受到干扰，并且 BTHS 成肌细胞中线粒体钙信号的急性刺激未能激活丙酮酸脱氢酶，这反过来会损害还原当量的产生并削弱线粒体生物能量学。总之，我们的研究结果表明线粒体钙信号传导的缺陷可能导致在 BTHS 患者中观察到的心脏和骨骼肌病变。我们表明，MICU1 依赖性线粒体钙摄取的动力学受到干扰，并且 BTHS 成肌细胞中线粒体钙信号的急性刺激未能激活丙酮酸脱氢酶，这反过来会损害还原当量的产生并削弱线粒体生物能量学。总之，我们的研究结果表明线粒体钙信号传导的缺陷可能导致在 BTHS 患者中观察到的心脏和骨骼肌病变。