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

Cell reports · 12 authors, 8 centres

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Inhibition of neddylation disrupted metabolic gene expression, impaired mitochondrial respiration, and suppressed fatty acid utilization, blocking the perinatal glycolysis-to-oxidative metabolism shift. The authors show HIF1α accumulates when neddylation is inhibited, and that neddylation of Cul2 and HIF1α normally promotes HIF1α ubiquitination and degradation. Limitations include possible off-target effects on the Hippo-YAP pathway, lack of single-cell transcriptomic resolution, and uncertainty about neddylation effects on contractility, T-tubule remodeling, and Ca2+ handling beyond metabolism.

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other

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cardiology

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ORIGINAL PAPER

PMC10029150

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

Cell reports

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ABSTRACT

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.

CITATION EXPORT

Jianqiu Zou, Wenjuan Wang, Yi Lu et al.. Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation. Cell reports. (2023). https://doi.org/10.1016/j.celrep.2023.112018

AUTHORS

12 · 8 CENTRES

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

1Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
2Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
3Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
4Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
5Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
6Department of Medicine, University of Iowa, 200 Hawkins Drive, CBRB 2270B, Iowa City, IA 52242, USA
7Division of Cardiology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
8Lead contact