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

doi:10.1016/j.celrep.2023.112018

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

Cell Rep. 2023 Jan 31;42(1):112018. doi: 10.1016/j.celrep.2023.112018. Epub 2023 Jan 19.

Authors

Jianqiu Zou¹, Wenjuan Wang², Yi Lu³, Juan Ayala¹, Kunzhe Dong⁴, Hongyi Zhou⁵, Jinxi Wang⁶, Weiqin Chen⁵, Neal L Weintraub¹, Jiliang Zhou⁶, Jie Li⁷, Huabo Su⁸

Affiliations

¹ Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
² 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.
³ 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.
⁴ Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
⁵ Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
⁶ Department of Medicine, University of Iowa, 200 Hawkins Drive, CBRB 2270B, Iowa City, IA 52242, USA.
⁷ 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.
⁸ 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. Electronic address: hsu@augusta.edu.

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.

Keywords: CP: Developmental biology; HIF1α; NAE1; cardiac maturation; metabolic transition; neddylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Energy Metabolism
Female
Glycolysis
Heart Failure* / metabolism
Humans
Infant, Newborn
Myocytes, Cardiac* / metabolism
Pregnancy
Protein Processing, Post-Translational

Abstract

Publication types

MeSH terms

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