Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy

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 Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin and Toren Finkel
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Nuo Sun: Columbus
Hayley Barta: Columbus
Samhita Chaudhuri: Columbus
Kangxuan Chen: 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
Shiori Sekine: University of Pittsburgh School of Medicine
Hannah Sanders: Columbus
Dominic Kolonay: Columbus
Mudra Patel: Columbus
Kedryn Baskin: Columbus
Harpreet Singh: Columbus
Pengyi Zhang: Columbus
Gang Xin: The Ohio State University Wexner Medical Center
Toren Finkel: University of Pittsburgh School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60670-z

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