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Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy

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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