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

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 <i>PPARGC1A</i>, 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 <i>SUCLG1</i>, <i>MDH2</i>, <i>HADHA</i>, and <i>HADHB</i> 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.