# Neddylation and cardiac protein quality control

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $451,035

## Abstract

PROJECT SUMMARY
 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 regulat...

## Key facts

- **NIH application ID:** 10064097
- **Project number:** 5R01HL124248-07
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Huabo Su
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,035
- **Award type:** 5
- **Project period:** 2014-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064097

## Citation

> US National Institutes of Health, RePORTER application 10064097, Neddylation and cardiac protein quality control (5R01HL124248-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064097. Licensed CC0.

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