PXD052216

PXD052216 is an original dataset announced via ProteomeXchange.

Title	Mitophagy Mitigates Mitochondrial Fatty Acid β-oxidation Deficient Cardiomyopathy
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-07-14
AnnouncementXML	Submission_2025-07-13_16:12:10.438.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nuo Sun
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-13 07:05:07	ID requested
⏵ 1	2025-07-13 16:12:11	announced

10.1038/s41467-025-60670-z;

Sun N, Barta H, Chaudhuri S, Chen K, Jin J, Luo H, Yang M, Krigman J, Zhang R, Sanghvi S, Sekine S, Sanders H, Kolonay D, Patel M, Baskin K, Singh H, Zhang P, Xin G, Finkel T, -oxidation deficient cardiomyopathy. Nat Commun, 16(1):5465(2025) [pubmed]

submitter keyword: Mitophagy

mitochondrial

fatty acid β-oxidation

USP30

Cardiomyopathy

PINK1

Parkin

Nuo Sun
contact affiliation	The Ohio State University
contact email	sun.2507@osu.edu
lab head
Nuo Sun
contact affiliation	The Ohio State University
contact email	sun.2507@osu.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/07/PXD052216

PRIDE project URI

• PRIDE
  1. PXD052216
     1. Label: PRIDE project
     2. Name: Mitophagy Mitigates Mitochondrial Fatty Acid β-oxidation Deficient Cardiomyopathy