Disruption of protein homeostasis causes cardiomyocyte (CM) dysfunction and death, and is increasingly recognized to play a causal role in human cardiomyopathies and heart failure. Ubiquitin (Ub) and Ub-like proteins modify diverse protein substrates and expand the functional diversity of the proteome. An extensive body of work has suggested the exciting potential of targeting these protein modifiers to combat cardiac disease. However, the functional role of NEDD8, a novel Ub-like protein, remains poorly understood in the heart. Neddylation covalently attaches NEDD8 to target proteins via NEDD8-specific E1-E2-E3 enzymes. Over the previous funding cycle, we discovered that neddylation is dysregulated in the failing hearts of patients and animal models of cardiac diseases. We further demonstrated that a balance between neddylation and deneddylation is essential to cardiac homeostasis, as evidenced by the fact that perturbation of deneddylation precipitated the heart to cardiomyopathy and heart failure, whereas blockade of neddylation in the developing heart caused ventricular noncompaction and perinatal lethality. Although it is becoming apparent that neddylation is essential for organ development, its functional importance in fully differentiated, postmitotic tissues is not clear. This grant addresses a novel linkage between neddylation and mitochondrial integrity in adult CMs. Pharmacological inhibition of neddylation promoted mitochondrial fusion, disrupted mitochondrial membrane potential and impaired mitochondrial respiration in neonatal CMs. Deletion of NAE1 (a regulatory subunit of the NEDD8 E1 enzyme) in adult CMs also resulted in mitochondrial elongation and impaired mitochondrial quality. Mechanistically, neddylation modifies various cellular proteins to regulate mitochondrial dynamics and mitophagy. Conditional knockout (KO) of NAE1 in adult mouse hearts resulted in dilated cardiomyopathy, heart failure, and ultimately premature death. In clinical trials, administration of the neddylation inhibitor MLN4924 to cancer patients elicited severe cardiotoxicity. These compelling published and preliminary data form the basis of our central hypothesis that neddylation is required for normal heart function through regulation of mitochondrial dynamics and mitophagy. Using the newly generated inducible NAE1KO mice and MLN4924, Aim 1 will establish the significance of neddylation in the adult healthy and failing heart and determine the impact of neddylation on mitochondrial function.
Aim 2 will dissect the molecular basis by which neddylation controls mitochondrial dynamics and will test if normalization of mitochondrial morphology benefits the NAE1KO heart.
Aim 3 will elucidate novel Parkin-independent mechanisms by which neddylation regulates mitophagy and test whether restoration of neddylation attenuates cardiac dysfunction in NAE1KO mice. This study will be the first to establish an unappreciated role for neddylation in regulating mitochondrial fitness and function in adult CMs. Moreover, it will provide novel insight into the potential cardiotoxicity of neddylation inhibitors that are currently being applied in cancer therapy, thus advancing the field of cardio-oncology.

Public Health Relevance

Heart disease remains a major health problem worldwide. This study will address the importance of a novel protein post-translational modification in the maintenance of heart function under resting and stressed conditions, and will investigate how this modification regulates the function of mitochondria, whose dysfunction is implicated in cardiac and other diseases. This research will also produce broadly applicable, basic biological insights.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Wong, Renee P
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Augusta University
Schools of Medicine
United States
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Teoh, Jian-Peng; Bayoumi, Ahmed S; Aonuma, Tatsuya et al. (2018) ?-arrestin-biased agonism of ?-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. J Mol Cell Cardiol 118:225-236
Li, Jie; Johnson, John A; Su, Huabo (2018) Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection. Curr Drug Targets 19:989-1002
Zou, Jianqiu; Ma, Wenxia; Li, Jie et al. (2018) Neddylation mediates ventricular chamber maturation through repression of Hippo signaling. Proc Natl Acad Sci U S A 115:E4101-E4110
Li, Jie; Yue, Guihua; Ma, Wenxia et al. (2018) Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure. Circ Heart Fail 11:e004917
Bayoumi, Ahmed S; Park, Kyoung-Mi; Wang, Yongchao et al. (2018) A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J Mol Cell Cardiol 114:72-82
Wen, Tong; Yin, Qin; Yu, Luyi et al. (2017) Characterization of mice carrying a conditional TEAD1 allele. Genesis 55:
Li, Jie; Ma, Wenxia; Yue, Guihua et al. (2017) Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy. J Mol Cell Cardiol 102:53-60
Bayoumi, Ahmed S; Teoh, Jian-Peng; Aonuma, Tatsuya et al. (2017) MicroRNA-532 protects the heart in acute myocardial infarction, and represses prss23, a positive regulator of endothelial-to-mesenchymal transition. Cardiovasc Res 113:1603-1614
Liu, Jinbao; Su, Huabo; Wang, Xuejun (2016) The COP9 signalosome coerces autophagy and the ubiquitin-proteasome system to police the heart. Autophagy 12:601-2
Li, Lei; Cao, Yu; Wu, Haitao et al. (2016) Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation. Neuron 92:1007-1019

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