Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses
Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses
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DOI：
10.1093/cvr/cvx095
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发表时间：
2017-08-01
影响因子：
10.8
通讯作者：
Kang, Dongchon
中科院分区：
文献类型：
--
作者：
Saito, Toshiro;Uchiumi, Takeshi;Kang, Dongchon
线粒体是一种重要的细胞器，致力于能量的产生。线粒体p32/C1qbp作为RNA和蛋白质的伴侣，与线粒体mRNA相互作用，在培养细胞系中通过调控线粒体翻译，对线粒体功能起着不可或缺的作用。然而，p32/ C1qbp在体内的确切作用尚不清楚，因为在全身性p32缺陷小鼠中存在胚胎致命性。本研究的目的是研究线粒体p32/ C1qbp在心脏中的生理功能。方法和结果我们利用Cre-loxP重组酶技术，通过他莫昔芬诱导的p32基因敲除或基因消融，研究了p32在小鼠产后心功能调节中的作用。与对照组小鼠的心脏相比，心肌细胞特异性p32缺失导致收缩功能障碍、心脏扩张和心脏纤维化。我们还发现COX1表达降低，耗氧量降低和氧化应激增加，表明这些小鼠在早期就有p32缺乏引起的心脏线粒体功能障碍。接下来，我们研究了心脏特异性p32缺陷小鼠的寿命。这些小鼠在12个月时开始死亡，它们的平均寿命与14个月相似。电镜显示p32缺陷小鼠心肌线粒体排列紊乱、增大，内部结构异常。我们观察到，与对照肌细胞相比，在p32缺失的肌细胞中，AMPKA被组成性磷酸化，4EBP-1和核糖体S6K的磷酸化较少，这表明哺乳动物雷帕霉素信号传导靶点受损。最后，我们发现分裂因子如FGF21和综合应激反应基因的表达水平显著增加。代谢分析表明，在p32缺陷的心脏中，尿素循环受损。结论线粒体p32蛋白在心肌细胞线粒体翻译和功能调控中起关键作用，从而影响心肌细胞的存活。
Aims Mitochondria are important organelles, dedicated to energy production. Mitochondrial p32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of p32/ C1qbp in vivo is poorly understood because of embryonic lethality in the systemic p32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial p32/ C1qbp in the heart.Methods and results We investigated the role of p32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against p32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of p32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by p32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific p32-deficient mice. The mice died beginning at 12 months and their median lifespan was similar to 14 months. Cardiac mitochondria in the p32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in p32-deficient compared with control myocytes, AMPKA was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the p32-deficient hearts.Conclusion These findings support a key role for mitochondrial p32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.