Tuesday, December 9, 2025 12/9/2025

Interplay between mitophagy and substrate utilization in heart failure progression

Award Number: R01HL160581
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/06/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

Group Awards By:

View Award Description

Interplay between mitophagy and substrate utilization in heart failure progression - PROJECT SUMMARY Mitochondrial dysfunction and altered mitochondrial metabolism have been implicated in the development of heart failure (HF). Mitophagy is a specialized autophagic pathway that mediates the lysosome-dependent clearance of damaged mitochondria, and is essential for mitochondrial quality control. However, our current knowledge regarding mitophagy in the heart and how it relates to myocardial metabolism is limited. Under normal conditions, the heart relies predominantly on fatty acid β-oxidation (FAO) to fuel ATP production. In contrast, a failing or hypertrophied heart usually shows impaired FAO and increased reliance on glucose utilization. Despite significant advancements in understanding the regulatory programs that attenuate FAO, it is unclear how shifts in myocardial substrate utilization contribute to the regulation of mitophagy. Therefore, this research proposal focuses on the functional significance of cardiac mitophagy in response to altered myocardial substrate utilization that occurs, for instance, in the setting of impaired FAO. The goal of this project is to delineate the novel mechanistic link between mitophagy and myocardial substrate utilization in the heart, as well as to determine whether mitophagy represents a novel mechanism and therapeutic target for the treatment of heart disease. These studies will be facilitated by our recently described mt-Keima mouse model to monitor in vivo cardiac mitophagy, as well as a set of innovative reagents to genetically and pharmacologically modulate mitophagic flux. To directly assess the role of FAO in the heart, we have generated mice with cardiomyocyte-specific deletion of CPT2 (CPT2-cKO), encoding a single gene required for FAO. We have demonstrated a decline in mitophagy precedes the development of impaired cardiac function in FAO-deficient hearts. Our genetic analyses suggest cardiac CPT2 deletion impairs the PTEN-induced putative kinase 1 (PINK1) signaling pathway, which positively regulates mitophagy through mitochondrial ubiquitination. Augmentation of mitophagy by modulating USP30, which mediates the reverse reaction, deubiquitination on mitochondria, mitigates the functional decline in FAO deficient hearts. Therefore, in Aim 1 of the proposed studies, our goal is to define the magnitude and Kinetics of cardiac mitophagy in response to impaired FAO, as well as to dissect the underlying molecular mechanisms connecting mitophagy to myocardial substrate utilization. In Aim 2 of the proposed studies, we will genetically and pharmacologically manipulate USP30 enzymatic function in the heart using mouse models that lack USP30 or are treated with a novel USP30 inhibitor. We will determine whether the detrimental cardiac phenotype, induced by cardiac CPT2 deletion or pressure overload, could be reversed, at least partially, by restoring mitophagy in cardiomyocytes via the inhibition of USP30. Completion of the proposed studies will produce critical insights into the role of mitophagy in normal cardiovascular physiology and in pathological conditions, and will fundamentally advance our understanding of the interaction between mitochondrial metabolism and mitochondrial quality control in the heart.


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 = $533,501 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	4	11/13/2024	NON-COMPETING CONTINUATION	$480,151
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	4	8/14/2025	NON-COMPETING CONTINUATION	$53,350
														Subtotal = $533,501

Issue Date FY: 2024 ( Subtotal = $522,831 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	3	6/24/2024	NON-COMPETING CONTINUATION	$42,680
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	3	11/6/2023	NON-COMPETING CONTINUATION	$480,151
														Subtotal = $522,831

Issue Date FY: 2023 ( Subtotal = $523,264 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	11/16/2022	NON-COMPETING CONTINUATION	$470,938
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	2	3/21/2023	NON-COMPETING CONTINUATION	$52,326
														Subtotal = $523,264

Issue Date FY: 2022 ( Subtotal = $546,264 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	12/6/2021	NEW	$546,264
														Subtotal = $546,264

Grand Total All Awards = $2,125,860

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Interplay between mitophagy and substrate utilization in heart failure progression

Award Number: R01HL160581

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/06/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer