Integrated Proteomic and Metabolomic Profiling Reveals Impaired Mitochondrial Oxidative Phosphorylation in Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is increasingly recognized as a disease of impaired myocardial energetics, but integrated proteomic–metabolomic data from human myocardium are scarce. This study combined quantitative proteomics and untargeted metabolomics to obtain a systems-level view of myocardial remodeling and to identify pathways jointly dysregulated at the protein and metabolite levels. Methods: Myocardial tissue from 7 patients with HCM who underwent surgical myectomy and 5 healthy control donors at Guangdong Provincial People’s Hospital was analyzed by data-independent acquisition-based quantitative proteomics and Liquid Chromatography-Tandem Mass Spectrometry–based untargeted metabolomics. Differentially expressed proteins (DEPs) and metabolites were identified using predefined fold change and statistical thresholds. Gene Ontology and pathways enrichment analyses were performed, and significantly enriched pathways from proteomics and metabolomics were intersected. Results: Proteomic profiling identified 165 DEPs and showed prominent enrichment of mitochondrial and oxidative phosphorylation–related terms, indicating extensive remodeling of respiratory chain complexes. Metabolomic analysis identified nearly 200 differential metabolites, with enrichment in purine metabolism and energy-sensing pathways, including AMPK and cGMP–PKG signaling. Intersecting 77 proteomic and 38 metabolomic pathways yielded seven shared pathways, among which oxidative phosphorylation emerged as a central node. Within this pathway, 23 of 24 proteins were downregulated, ATP5PO was upregulated, and NAD and ADP were decreased, consistent with impaired mitochondrial ATP production. Conclusion: Integrated proteomic and metabolomic profiling of HCM myocardium provides convergent evidence that mitochondrial oxidative phosphorylation is a core site of energetic dysfunction, highlighting mitochondrial and energy related pathways as potential targets for future mechanistic and therapeutic studies.