Rationale: Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM). Methods: Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed. Results: In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets. Conclusion: Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.

中文翻译：

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Hippo 信号通路的激活介导小鼠线粒体功能障碍和扩张型心肌病。

基本原理：线粒体功能障碍促进心力衰竭发展形成治疗靶点，但所涉及的机制仍不清楚。我们研究了 Hippo 信号通路是否介导导致扩张型心肌病 (DCM) 发作的线粒体异常。方法：研究了由于 Hippo 通路激酶 Mst1 过表达而患有 DCM 的小鼠。DCM 表型在成年动物中很明显，但收缩功能障碍在出生后 3 周被确定为 DCM 的早期迹象。采用电子显微镜、多组学和生化分析。结果：在 3 周和成年 DCM 小鼠心脏中，心肌细胞线粒体表现出明显的结构异常，尺寸更小，数量更多。RNA 测序揭示了核 DNA (nDNA) 编码基因组的全面抑制，这些基因组涉及线粒体周转和代谢的各个方面。两个年龄的 DCM 心脏中多种线粒体蛋白的蛋白质水平较低，证实了心脏转录组的变化。线粒体 DNA 编码的基因也被下调。显然是由于抑制了 ndna 编码的转录因子。脂质组学发现心磷脂酰基链发生重塑，酰基肉碱含量增加，但辅酶 Q10 水平降低。线粒体功能障碍的特点是 ATP 含量较低，乳酸、支链氨基酸和活性氧化物质水平升高。从机制上讲，抑制性 YAP 磷酸化增强，这与转录因子 TEAD1 的结合减弱有关。许多抑制的线粒体基因被鉴定为 YAP 靶标。结论：Hippo信号激活通过抑制线粒体基因介导线粒体损伤，从而促进DCM的发展。因此，Hippo 通路代表了针对心肌病线粒体功能障碍的治疗靶点。