Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation

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 un-clear. 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. Mechanisti-cally, we find that neddylation is needed for the perinatal metabolic transition from glycolytic to oxidative metabolism in cardiomyocytes. Further, we show that HIF1a is a putative neddylation target and that inhibi-tion of neddylation accumulates HIF1a 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.

Automated summary

Cardiac maturation is regulated by neddylation, a post-translational modification process. Mosaic deletion of NAE1, a necessary enzyme for neddylation, in neonatal hearts leads to cardiomyopathy and heart failure. Neddylation is involved in transverse tubule formation, physiological hypertrophy, and fetal-to-adult isoform switching, promoting cardiac maturation through oxidative metabolism.