Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xian Jiaotong University Health Science Center, Xian, China.
School of Life and Environmental Sciences, Deakin University, Geelong, Victoria, Australia.
Theranostics. 2021 Aug 21;11(18):8993-9008. doi: 10.7150/thno.62302. eCollection 2021.
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). 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. 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. 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.
线粒体功能障碍促进心力衰竭的发展，形成治疗靶点，但其中涉及的机制尚不清楚。我们研究了 Hippo 信号通路是否介导线粒体异常，导致扩张型心肌病（DCM）的发生。研究了 Hippo 通路激酶 Mst1 过表达导致 DCM 的小鼠。在成年动物中表现出 DCM 表型，但在出生后 3 周时发现收缩功能障碍是 DCM 的早期迹象。采用电子显微镜、多组学和生化分析方法。在 3 周龄和成年 DCM 小鼠心脏中，心肌细胞线粒体表现出明显的结构异常，体积更小，数量更多。RNA 测序显示，核 DNA（nDNA）编码的与线粒体周转和代谢各个方面相关的基因集受到全面抑制。在两个年龄段的 DCM 心脏中，多种线粒体蛋白的蛋白水平降低，证实了心脏转录组的变化。线粒体 DNA 编码的基因也下调；显然是由于 nDNA 编码转录因子的抑制。脂质组学鉴定出心磷脂酰基链的重塑、酰基辅酶 A 含量增加，但辅酶 Q10 水平降低。线粒体功能障碍的特征是 ATP 含量降低，乳酸、支链氨基酸和活性氧物质水平升高。从机制上讲，抑制性 YAP 磷酸化增强，与转录因子 TEAD1 结合减弱有关。鉴定出许多受抑制的线粒体基因是 YAP 的靶点。Hippo 信号通路的激活通过抑制线粒体基因介导线粒体损伤，这可导致 DCM 的发展。因此，Hippo 通路是治疗心肌病中线粒体功能障碍的一个靶点。
