Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency-induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 in cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart field-derived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes and embryonic lethality. By characterizing this model, we reveal an AMPK-SIRT7-GABPB axis that relays the reduced cellular energy level to decrease transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first genetic evidence in mouse that Drp1 is essential for RV development. Our research provides further mechanistic insight into how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.

中文翻译：

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Drp1 调节胚胎心脏核糖体蛋白基因的转录。

线粒体功能障碍会导致严重的先天性心脏异常和产前/新生儿死亡。缺乏关于线粒体异常如何影响心脏发生的足够知识，是针对线粒体缺陷诱导的先天性心肌病的临床应用发展的主要障碍。受裂变和融合调控的线粒体形态在决定线粒体活性方面起着关键作用。Dnm1l 编码与动力蛋白相关的 GTP 酶 Drp1，它是线粒体裂变所必需的。为了研究 Drp1 在胚胎代谢转变期间心脏发生中的作用，我们特别灭活了第二心脏场衍生结构中的 Dnm1l。右心室 (RV) 中的突变心肌细胞在线粒体形态、超微结构和活性方面显示出严重缺陷。这些缺陷导致细胞死亡增加、细胞存活减少、心肌细胞紊乱和胚胎致死。通过表征该模型，我们揭示了一个 AMPK-SIRT7-GABPB 轴，该轴传递降低的细胞能量水平以减少心肌细胞中核糖体蛋白基因的转录。因此，我们在小鼠中提供了第一个遗传证据，证明 Drp1 对 RV 发育至关重要。我们的研究为线粒体功能障碍如何在心脏发生过程中导致病理性分子和细胞改变提供了进一步的机制洞察。我们揭示了一个 AMPK-SIRT7-GABPB 轴，该轴传递降低的细胞能量水平以减少心肌细胞中核糖体蛋白基因的转录。因此，我们在小鼠中提供了第一个遗传证据，证明 Drp1 对 RV 发育至关重要。我们的研究为线粒体功能障碍如何在心脏发生过程中导致病理性分子和细胞改变提供了进一步的机制洞察。我们揭示了一个 AMPK-SIRT7-GABPB 轴，该轴传递降低的细胞能量水平以减少心肌细胞中核糖体蛋白基因的转录。因此，我们在小鼠中提供了第一个遗传证据，证明 Drp1 对 RV 发育至关重要。我们的研究为线粒体功能障碍如何在心脏发生过程中导致病理性分子和细胞改变提供了进一步的机制洞察。