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

Abstract

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 1 Pg. 112018 (01 31 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 36662623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Topics

• Humans
• Pregnancy
• Female
• Infant, Newborn
• Myocytes, Cardiac (metabolism)
• Heart Failure (metabolism)
• Energy Metabolism
• Protein Processing, Post-Translational
• Glycolysis