A novel posttranslational mechanism underlying cardiac metabolic maturation

In developing hearts, changes in cardiac metabolic milieu during the perinatal period trigger a metabolic shift from fetal-type glycolysis to adult-type fatty acid oxidation. Defects in this perinatal metabolic remodeling has been linked to congenital heart disease (CHD), a leading cause of birth-related mortality and morbidity worldwide. The regulatory mechanisms underlying the metabolic reprogramming during cardiac development remains largely unknown. We have recently identified an essential role of NEDD8, a novel ubiquitin-like protein, in regulation of cardiomyocyte (CM) metabolic maturation and function. Posttranslational modifications by ubiquitin and ubiquitin-like proteins play important roles in the regulation of protein functions. Conjugation of NEDD8 to target proteins (neddylation) requires the NEDD8 specific E1, E2 and E3 enzymes and can be reversed by the actions of the NEDD8 proteases. The only NEDD8 E1 identified so far is a heterodimer of NEDD8 activating enzyme 1 (NAE1) and UBA3. To date, the importance of neddylation in cardiac development has not been explored. Our pilot studies revealed that neddylation is developmentally downregulated in mouse hearts. While mice with germline deficiency of NAE1 died during early embryonic development stage, cardiomyocyte-restricted knockout of NAE1 caused rapid development of dilated cardiomyopathy and heart failure, leading to neonatal lethality of mice. The striking cardiac phenotypes was accompanied by defective cardiac energy metabolism and accumulation of hypoxia-inducible factor 1 alpha (HIF1a), an important regulator of cardiac metabolic function that is found to be a NEDD8 target. Thus our overall hypothesis is that NAE1 is essential for maintaining cardiac metabolic homeostasis through fine-tuning HIF1a signaling. To test this hypothesis, we will determine the role of neddylation in cardiac metabolism in mouse hearts and cultured cardiomyocytes (Aim 1), We will also investigate the significance of NAE1-mediated HIF1a neddylation in CM metabolism (Aim 2). Positive findings of this project will provide novel mechanisms underlying cardiac development and maturation, and the control of cardiac metabolism, thereby facilitating the development of therapies for CHD and other heart diseases associated with metabolic dysfunction. (AHA Program: Postdoctoral Fellowship)