Mitochondria supply ~90% of the ATP required for contractile function in cardiac cells. While adult cardiomyocytes preferentially utilize fatty acids as a fuel source for oxidative phosphorylation, cardiac mitochondria can switch to other substrates when required. This change is driven in part by a combination of extracellular and intracellular signal transduction pathways that alter mitochondrial gene expression and enzymatic activity. The mechanisms by which extracellular metabolic information is conveyed to cardiac mitochondria are not currently well defined. Recent work has shown that adropin – a liver-secreted peptide hormone – can induce changes in mitochondrial fuel substrate utilization in skeletal muscle, leading to increased glucose use. In this study, we examined whether adropin could regulate mitochondrial glucose utilization pathways in cardiac cells. We show that stimulation of cultured cardiac cells with adropin leads to decreased expression of the pyruvate dehydrogenase (PDH) negative regulator PDK4, which reduces inhibitory PDH phosphorylation. The downregulation of PDK4 expression by adropin is lost when GPR19 – a putative adropin receptor – is genetically depleted in H9c2 cells. Loss of GRP19 expression alone increased PDK4 expression, leading to a reduction in mitochondrial respiration. Finally, we show that adropin-mediated GPR19 signaling relies on the p44/42 MAPK pathway, and that pharmacological disruption of this pathway blocks the effects of adropin on PDK4 in cardiac cells. These findings suggest that adropin may be a key regulator of fuel substrate utilization in the heart, and implicates an orphan G-protein coupled receptor in a novel signaling pathway controlling mitochondrial fuel metabolism.

线粒体提供心脏细胞收缩功能所需的ATP的90％。虽然成年心肌细胞优先利用脂肪酸作为氧化磷酸化的燃料来源，但在需要时，心脏线粒体可以转换为其他底物。这种变化部分是由改变线粒体基因表达和酶活性的细胞外和细胞内信号转导途径共同驱动的。目前尚不明确将细胞外代谢信息传递到心脏线粒体的机制。最近的研究表明，降钙素-一种肝脏分泌的肽激素-可以诱导骨骼肌线粒体燃料底物利用率的变化，从而导致葡萄糖的使用增加。在这项研究中，我们检查了降钙素是否可以调节心脏细胞中的线粒体葡萄糖利用途径。我们显示，用降钙素刺激培养的心肌细胞会导致丙酮酸脱氢酶（PDH）负调节剂PDK4的表达降低，从而降低抑制性PDH磷酸化。当H9c2细胞中的GPR19（一种假定的adropin受体）基因缺失时，adropin会降低PDK4表达的下调。单独的GRP19表达缺失会增加PDK4表达，从而导致线粒体呼吸减少。最后，我们显示了adropin介导的GPR19信号传导依赖于p44 / 42 MAPK途径，并且该途径的药理学破坏阻断了adropin对心脏细胞中PDK4的影响。这些发现表明，adropin可能是心脏中燃料底物利用的关键调节剂，