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 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.