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Mitophagy Mitigates Mitochondrial Fatty Acid β-oxidation Deficient Cardiomyopathy

ABSTRACT: Cardiomyocytes rely on mitochondrial fatty acid β-oxidation (FAO) for ATP production in the healthy heart but can exhibit marked metabolic flexibility in response to diverse physiological circumstances. Mutations or deficiencies in FAO enzymes can lead to a spectrum of symptoms, ranging from muscle weakness to severe cardiomyopathy, and, in some instances, culminate in neonatal/infantile mortality. It is generally believed that under FAO deficit, mitochondria encounter stress, potentially triggering the initiation of mitophagy, a process crucial for maintaining mitochondrial quality. We explored the link between FAO deficiency and mitophagy utilizing FAO-deficient mice generated through cardiomyocyte-specific deletion of the Carnitine Palmitoyltransferase 2 (CPT2). Intriguingly, our findings contradicted the prevailing hypothesis, revealing an unexpected decline in mitophagy in FAO-deficient hearts. Employing an integrated approach involving quantitative proteomics, metabolomics, and transcriptomics assays, we identified suppressed a PINK1/Parkin signaling pathway in CPT2-deficient heart tissues. Our study demonstrated that the loss of cardiac FAO impairs the PINK1 pathway by modulating the mitochondrial rhomboid protease PARL (presenilin-associated rhomboid-like protein). Furthermore, inhibiting USP30, a mitochondrial deubiquitinating enzyme antagonizing PINK1/Parkin function, restored cardiac mitophagy, thereby alleviating FAO-associated cardiac dysfunction. Notably, the deletion of USP30 conferred a significant survival advantage to FAO-deficient animals, doubling the median survival and substantially improving the maximum survival rate. The study unveiled a novel connection between FAO and PINK1-dependent mitophagy, presenting a potential therapeutic avenue for addressing FAO-deficient cardiomyopathies.

ORGANISM(S): Mus musculus

PROVIDER: GSE266487 | GEO | 2025/05/02

REPOSITORIES: GEO

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Mitophagy Mitigates Mitochondrial Fatty Acid β-oxidation Deficient Cardiomyopathy

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