Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Division of Cardiology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Am J Physiol Heart Circ Physiol. 2020 Jul 1;319(1):H89-H99. doi: 10.1152/ajpheart.00732.2019. Epub 2020 Jun 5.
Mitochondrial dysfunction occurs in most forms of heart failure. We have previously reported that Tead1, the transcriptional effector of Hippo pathway, is critical for maintaining adult cardiomyocyte function, and its deletion in adult heart results in lethal acute dilated cardiomyopathy. Growing lines of evidence indicate that Hippo pathway plays a role in regulating mitochondrial function, although its role in cardiomyocytes is unknown. Here, we show that Tead1 plays a critical role in regulating mitochondrial OXPHOS in cardiomyocytes. Assessment of mitochondrial bioenergetics in isolated mitochondria from adult hearts showed that loss of Tead1 led to a significant decrease in respiratory rates, with both palmitoylcarnitine and pyruvate/malate substrates, and was associated with reduced electron transport chain complex I activity and expression. Transcriptomic analysis from Tead1-knockout myocardium revealed genes encoding oxidative phosphorylation, TCA cycle, and fatty acid oxidation proteins as the top differentially enriched gene sets. Ex vivo loss of function of Tead1 in primary cardiomyocytes also showed diminished aerobic respiration and maximal mitochondrial oxygen consumption capacity, demonstrating that Tead1 regulation of OXPHOS in cardiomyocytes is cell autonomous. Taken together, our data demonstrate that Tead1 is a crucial transcriptional node that is a cell-autonomous regulator, a large network of mitochondrial function and biogenesis related genes essential for maintaining mitochondrial function and adult cardiomyocyte homeostasis. Mitochondrial dysfunction constitutes an important aspect of heart failure etiopathogenesis and progression. However, the molecular mechanisms are still largely unknown. Growing lines of evidence indicate that Hippo-Tead pathway plays a role in cellular bioenergetics. This study reveals the novel role of Tead1, the downstream transcriptional effector of Hippo pathway, as a novel regulator of mitochondrial oxidative phosphorylation and in vivo cardiomyocyte energy metabolism, thus providing a potential therapeutic target for modulating mitochondrial function and enhancing cytoprotection of cardiomyocytes.
线粒体功能障碍发生在大多数形式的心力衰竭中。我们之前曾报道过，Hippo 通路的转录效应因子 Tead1 对于维持成年心肌细胞的功能至关重要，其在成年心脏中的缺失会导致致命性急性扩张型心肌病。越来越多的证据表明 Hippo 通路在调节线粒体功能方面发挥作用，尽管其在心肌细胞中的作用尚不清楚。在这里，我们表明 Tead1 在调节心肌细胞中线粒体 OXPHOS 中发挥关键作用。评估来自成年心脏的分离线粒体中的线粒体生物能学表明，Tead1 的缺失导致呼吸率显著下降，使用棕榈酰肉碱和丙酮酸/苹果酸底物时均如此，并且与电子传递链复合物 I 活性和表达降低相关。Tead1 敲除心肌中的转录组分析显示，编码氧化磷酸化、三羧酸循环和脂肪酸氧化蛋白的基因是差异表达基因集的前 5 个。在原代心肌细胞中进行 Tead1 功能丧失的离体实验也显示有氧呼吸和最大线粒体耗氧量能力降低，表明 Tead1 对心肌细胞中 OXPHOS 的调节是细胞自主的。综上所述，我们的数据表明 Tead1 是一个关键的转录节点，是一个细胞自主的调节因子，是一个与维持线粒体功能和成年心肌细胞稳态相关的大型线粒体功能和生物发生相关基因网络的关键调节因子。线粒体功能障碍是心力衰竭发病机制和进展的一个重要方面。然而，其分子机制在很大程度上仍不清楚。越来越多的证据表明 Hippo-Tead 通路在细胞生物能学中发挥作用。这项研究揭示了 Hippo 通路的下游转录效应因子 Tead1 作为一种新的线粒体氧化磷酸化调节因子以及体内心肌细胞能量代谢的新作用，从而为调节线粒体功能和增强心肌细胞的细胞保护作用提供了一个潜在的治疗靶点。
