# Mitochondrial quality control in the heart

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2023 · $596,841

## Abstract

PROJECT SUMMARY
 Adult cardiomyocytes (CMs) are critically dependent on the proper function of mitochondria to supply the fuel
for contraction (ATP) and to regulate other essential cellular processes. Mitochondrial health is maintained by a
selective form of autophagy, termed mitophagy, which removes Ubiquitin (Ub)-labeled damaged mitochondria.
Our current understanding of mitophagy is based on the actions of two key proteins, the Ub ligase Parkin and
kinase PINK1, which mark dysfunctional mitochondria for degradation via a phosphorylated Ub chain.
Surprisingly, ablation of Parkin failed to impact homeostatic mitophagy or cardiac function in both young and
ageing mice, suggesting the existence of yet to be identified, Parkin-independent mechanisms control
mitochondrial turnover in CMs. Given robust mitophagic activity in adult hearts and the deleterious impact of
impaired mitophagy in various cardiac diseases, there is a growing need to identify novel, Parkin-independent
regulators of mitophagy in the heart. In preliminary data for this proposal, we document a new mechanism linking
Cullin-Ring Ub ligase 5 (CRL5) with mitochondrial quality control in the heart. CRL5 is a multi-protein complex
comprised of the RING box protein RBX2, scaffold protein Culllin 5 (Cul5), adaptor proteins Elongin B/C, and
various substrate receptor proteins. Activation of CRL5 requires the neddylation of Cul5, a process that
conjugates the small Ub-like protein, NEDD8 to target proteins. By controlling the turnover of its protein
substrates, CRL5 participates in several biological processes and human diseases, but a role in the heart is not
yet known. Inhibition of neddylation (upstream signaling that governs CRL5 activity), robustly suppressed
mitochondrial ubiquitination and mitophagy, and mice deficient in neddylation develop heart failure due to
impaired mitophagy and mitochondrial dysfunction. Proteomics analysis identifies RBX2 and Cul5 are associated
with mitochondria in homeostasis; and their recruitment to mitochondria is upregulated following mitochondria
damage. RBX2 is required for mitochondrial ubiquitination and turnover, and its actions in mitochondria are
independent of Parkin but are recapitulated by Cul5. Moreover, deletion of RBX2 in adult mice provokes
accumulation of damaged mitochondria and leads to heart failure. These findings support our central hypothesis
that RBX2-CRL5 Ub ligase mediates mitochondrial ubiquitination and mitophagy to regulate cardiac myocyte
function and survival in homeostasis and under stress. Three aims are proposed. Aim 1 will define the role of
RBX2-CRL5 in mitochondrial turnover in the healthy normal heart using RBX2- and Cul5- deficient mice. Aim 2
will identify the molecular underpinnings of CRL5-mediated mitophagy by identifying its substrate receptors,
substrates and scaffold proteins in mitochondria and by investigating the interplay between CRL5 and PINK1.
Aim 3 will test the feasibility of modulation of RBX2 to imp...

## Key facts

- **NIH application ID:** 10666641
- **Project number:** 5R01HL165205-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Huabo Su
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $596,841
- **Award type:** 5
- **Project period:** 2022-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10666641

## Citation

> US National Institutes of Health, RePORTER application 10666641, Mitochondrial quality control in the heart (5R01HL165205-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10666641. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*