Congenital heart diseases are the most common birth defects around the world. Emerging evidence suggests that mitochondrial homeostasis is required for normal heart development. In mitochondria, a series of molecular chaperones including heat shock protein 60 (HSP60) are engaged in assisting the import and folding of mitochondrial proteins. However, it remains largely obscure whether and how these mitochondrial chaperones regulate cardiac development. Here, we generated a cardiac-specific deletion mouse model by αMHC-Cre and investigated the role of HSP60 in cardiac development. We observed that deletion of HSP60 in embryonic cardiomyocytes resulted in abnormal heart development and embryonic lethality, characterized by reduced cardiac cell proliferation and thinner ventricular walls, highlighting an essential role of cardiac HSP60 in embryonic heart development and survival. Our results also demonstrated that HSP60 deficiency caused significant downregulation of mitochondrial ETC subunits and induced mitochondrial stress. Analysis of gene expression revealed that P21 that negatively regulates cell proliferation is significantly upregulated in HSP60 knockout hearts. Moreover, HSP60 deficiency induced activation of eIF2α-ATF4 pathway, further indicating the underlying mitochondrial stress in cardiomyocytes after HSP60 deletion. Taken together, our study demonstrated that regular function of mitochondrial chaperones is pivotal for maintaining normal mitochondrial homeostasis and embryonic heart development.

中文翻译：

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心脏特异性缺失热休克蛋白 60 会诱导线粒体应激并扰乱小鼠心脏发育

先天性心脏病是世界上最常见的出生缺陷。新的证据表明，线粒体稳态是正常心脏发育所必需的。在线粒体中，包括热休克蛋白60（HSP60）在内的一系列分子伴侣参与协助线粒体蛋白的输入和折叠。然而，这些线粒体伴侣是否以及如何调节心脏发育仍然在很大程度上不清楚。在这里，我们通过 αMHC-Cre 构建了心脏特异性缺失小鼠模型，并研究了 HSP60 在心脏发育中的作用。我们观察到，胚胎心肌细胞中 HSP60 的缺失会导致心脏发育异常和胚胎死亡，其特点是心肌细胞增殖减少和心室壁变薄，这凸显了心脏 HSP60 在胚胎心脏发育和存活中的重要作用。我们的结果还表明，HSP60 缺陷导致线粒体 ETC 亚基显着下调并诱导线粒体应激。基因表达分析表明，负调节细胞增殖的 P21 在 HSP60 敲除心脏中显着上调。此外，HSP60缺陷诱导eIF2α-ATF4通路的激活，进一步表明HSP60缺失后心肌细胞中潜在的线粒体应激。综上所述，我们的研究表明，线粒体伴侣的正常功能对于维持正常的线粒体稳态和胚胎心脏发育至关重要。