Author
Listed:
- Nuo Sun
(Columbus
Columbus)
- Hayley Barta
(Columbus
Columbus)
- Samhita Chaudhuri
(Columbus
Columbus)
- Kangxuan Chen
(Columbus
Columbus)
- Jiacheng Jin
(The Ohio State University Wexner Medical Center)
- Hongke Luo
(Columbus)
- Mingchong Yang
(Columbus)
- Judith Krigman
(Columbus)
- Ruohan Zhang
(Columbus)
- Shridhar Sanghvi
(Columbus
Columbus)
- Shiori Sekine
(University of Pittsburgh School of Medicine)
- Hannah Sanders
(Columbus
Columbus)
- Dominic Kolonay
(Columbus
Columbus)
- Mudra Patel
(Columbus
Columbus)
- Kedryn Baskin
(Columbus
Columbus)
- Harpreet Singh
(Columbus
Columbus)
- Pengyi Zhang
(Columbus)
- Gang Xin
(The Ohio State University Wexner Medical Center)
- Toren Finkel
(University of Pittsburgh School of Medicine)
Abstract
The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
Suggested Citation
Nuo Sun & Hayley Barta & Samhita Chaudhuri & Kangxuan Chen & Jiacheng Jin & Hongke Luo & Mingchong Yang & Judith Krigman & Ruohan Zhang & Shridhar Sanghvi & Shiori Sekine & Hannah Sanders & Dominic Ko, 2025.
"Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy,"
Nature Communications, Nature, vol. 16(1), pages 1-15, December.
Handle:
RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60670-z
DOI: 10.1038/s41467-025-60670-z
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