Thursday, September 18, 2025 9/18/2025

Mitochondrial quality control in the heart

Award Number: R01HL165205
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mitochondrial quality control in the heart - 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 improve mitophagy and cardiac injury in pressure- overloaded hearts. This study is significant as it will identify CRL5 as a mitochondrial Ub ligase to maintain mitochondrial integrity and thus provide potential therapeutic targets for treatment of heart failure.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $596,841 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	4	8/29/2025	NON-COMPETING CONTINUATION	$596,841
														Subtotal = $596,841

Issue Date FY: 2024 ( Subtotal = $584,904 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	6/10/2024	NON-COMPETING CONTINUATION	$584,904
														Subtotal = $584,904

Issue Date FY: 2023 ( Subtotal = $596,841 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	6/7/2023	NON-COMPETING CONTINUATION	$596,841
														Subtotal = $596,841

Issue Date FY: 2022 ( Subtotal = $596,841 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	7/15/2022	NEW	$596,841
														Subtotal = $596,841

Grand Total All Awards = $2,375,427

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Mitochondrial quality control in the heart

Award Number: R01HL165205

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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