Dataset Information

Mitophagy Mitigates Mitochondrial Fatty Acid β-oxidation Deficient Cardiomyopathy

ABSTRACT: The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) for ATP production but can exhibit marked metabolic flexibility in response to diverse physiological and pathological circumstances 1-4. 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 5. It is generally believed that with a FAO deficit, mitochondria encounter stress, 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 carnitine palmitoyltransferase 2 (CPT2). Intriguingly, our findings revealed an unexpected decline in mitophagy in FAO-deficient hearts. Employing an integrated approach involving quantitative proteomics, metabolomics, and transcriptomics assays, we identified a suppressed PINK1/Parkin signaling pathway in CPT2-deficient heart tissues. We demonstrate that the loss of cardiac FAO impairs the PINK1 pathway by modulating the mitochondrial rhomboid protease PARL (presenilin-associated rhomboid-like protein). Furthermore, we show that inhibiting USP30, a mitochondrial deubiquitinating enzyme antagonizing PINK1/Parkin function, restores cardiac mitophagy, thereby alleviating FAO deficiency-associated cardiac dysfunction. Notably, the deletion of USP30 confers a significant survival advantage to FAO-deficient animals, doubling the median survival and substantially improving the maximum survival rate. This study therefore unveils a novel connection between FAO and PINK1-dependent mitophagy. These findings also delineate a potential therapeutic avenue for addressing rare FAO-deficient cardiomyopathies, as well as a potential strategy for more routine heart failure, a condition often characterized by impaired fatty acid metabolism.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Nuo Sun

LAB HEAD: Nuo Sun

PROVIDER: PXD052216 | Pride | 2025-07-14

REPOSITORIES: Pride

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Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.

Sun Nuo N Barta Hayley H Chaudhuri Samhita S Chen Kangxuan K Jin Jiacheng J Luo Hongke H Yang Mingchong M Krigman Judith J Zhang Ruohan R Sanghvi Shridhar S Sekine Shiori S Sanders Hannah H Kolonay Dominic D Patel Mudra M Baskin Kedryn K Singh Harpreet H Zhang Pengyi P Xin Gang G Finkel Toren T

Nature communications 20250701 1

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 hea ...[more]

PMID: 40593619

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Project description:Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. While the role of ubiquitin (Ub) ligase PARKIN in mitophagy has been extensively studied, increasing evidence suggests the existence of PARKIN-independent mitophagy in highly metabolically active organs such as the heart. Here, we identify a crucial role for Cullin-RING Ub ligase 5 (CRL5) in basal mitochondrial turnover in cardiomyocytes. CRL5 is a multi-subunit Ub ligase comprised by the catalytic RING box protein RBX2 (also known as SAG), scaffold protein Cullin 5 (CUL5), and a substrate-recognizing receptor. Analysis of the mitochondrial outer membrane-interacting proteome uncovered a robust association of CRLs with mitochondria. Subcellular fractionation, immunostaining, and immunogold electron microscopy established that RBX2 and Cul5, two core components of CRL5, localizes to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, and increased cell death in cardiomyocytes. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. Notably, the action of RBX2 in mitochondria is not dependent on PARKIN, and PARKIN gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria. Proteomics and biochemical analyses further revealed a global impact of RBX2 deficiency on the mitochondrial proteome and identified several mitochondrial proteins as its putative substrates. These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that controls mitophagy under physiological conditions in a PARKIN-independent, PINK1-dependent manner, thereby regulating cardiac homeostasis.

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