Work

Mitochondrial metabolic remodeling and multi-omics profiling identify plasma biomarkers of myocardial infarction

Year: 2025

Type: article

Abstract: Mitochondrial dysfunction is a hallmark of myocardial infarction (MI), yet the molecular mechanisms linking metabolic reprogramming in the ischemic myocardium to systemic biomarker signatures remain incompletely understood. In this study, we employed a data-independent acquisition mass spectrometry (SWATH-MS) strategy integrating multi-omics analysis with upstream regulatory network analysis to investigate mitochondrial energy pathway alterations in a preclinical ovine model of MI. Proteomic profiling of infarcted myocardium revealed a pronounced shift from oxidative phosphorylation to glycolysis, accompanied by coordinated suppression of mitochondrial fatty acid β-oxidation enzymes. This metabolic reprogramming was strongly associated with four upstream master regulators, most notably predicted inhibition and significant transcriptional downregulation of PPARGC1A , a key coactivator of mitochondrial biogenesis and oxidative metabolism, indicating disrupted mitochondrial energy homeostasis and impaired adaptive responses in ischemic cardiomyocytes. Parallel plasma proteomic analysis identified a distinct panel of differentially expressed proteins enriched in pathways related to carbon metabolism, amino acid biosynthesis, and cardiac muscle contraction. Notably, mitochondrial metabolic enzymes such as SUCLG1 , MDH2 , HADHA , and HADHB were significantly downregulated at both the transcript and protein levels in cardiac tissue, while their protein abundance was markedly increased in plasma post-MI, highlighting their potential as circulating biomarkers of mitochondrial dysfunction. These findings provide mechanistic insight into the energy metabolic remodeling that occurs during myocardial ischemic injury and establish a systems-level framework for linking tissue-specific mitochondrial alterations with accessible plasma biomarkers. This study supports the translational potential of targeting mitochondrial pathways for diagnostic and therapeutic strategies in ischemic heart disease. • Mitochondrial metabolic remodeling contributes to cardiomyocyte death post-MI. • TCA cycle, OXPHOS, and fatty acid oxidation enzymes are downregulated. • Inhibited PPARGC1A disrupts mitochondrial energy homeostasis in ischemic heart. • SUCLG1, MDH2, HADHA, and HADHB are altered in tissue and plasma post-MI.

Source: Journal of Molecular and Cellular Cardiology Plus

DOI: 10.1016/j.jmccpl.2025.100827

Authors: Selvam Paramasivan, Mitchell C. Lock, Roberto A. Barrero, Paul C. Mills, Janna L. Morrison, Pawel Sadowski