Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation
Jianqiu Zou,
Wenjuan Wang,
Yi Lu,
Juan Ayala,
Kunzhe Dong,
Hongyi Zhou,
Jinxi Wang,
Weiqin Chen,
Neal L. Weintraub,
Jiliang Zhou,
Jie Li,
Huabo Su
Affiliations
Jianqiu Zou
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Wenjuan Wang
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
Yi Lu
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
Juan Ayala
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Kunzhe Dong
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Hongyi Zhou
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Jinxi Wang
Department of Medicine, University of Iowa, 200 Hawkins Drive, CBRB 2270B, Iowa City, IA 52242, USA
Weiqin Chen
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Neal L. Weintraub
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Jiliang Zhou
Department of Medicine, University of Iowa, 200 Hawkins Drive, CBRB 2270B, Iowa City, IA 52242, USA
Jie Li
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Division of Cardiology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Huabo Su
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Corresponding author
Summary: Cardiac maturation is crucial for postnatal cardiac development and is increasingly known to be regulated by a series of transcription factors. However, post-translational mechanisms regulating this process remain unclear. Here we report the indispensable role of neddylation in cardiac maturation. Mosaic deletion of NAE1, an essential enzyme for neddylation, in neonatal hearts results in the rapid development of cardiomyopathy and heart failure. NAE1 deficiency disrupts transverse tubule formation, inhibits physiological hypertrophy, and represses fetal-to-adult isoform switching, thus culminating in cardiomyocyte immaturation. Mechanistically, we find that neddylation is needed for the perinatal metabolic transition from glycolytic to oxidative metabolism in cardiomyocytes. Further, we show that HIF1α is a putative neddylation target and that inhibition of neddylation accumulates HIF1α and impairs fatty acid utilization and bioenergetics in cardiomyocytes. Together, our data show neddylation is required for cardiomyocyte maturation through promoting oxidative metabolism in the developing heart.
