Functional Changes in Mitochondrial Subpopulations of Left Ventricular Cardiomyocytes in Post-Infarction Rats During
Sergei A Fedotov1, Andrei V Stepanov2,3, Galina A Sakuta4
1Laboratory of Toxinology and Molecular Systematics, L.A. Orbeli Institute of Physiology, National Academy of Sciences, 0028 Yerevan, Armenia.
Background:
Cardiovascular diseases remain a leading cause of mortality worldwide, with myocardial infarction (MI) being the most severe form. Despite advances in treatment, MI is still associated with an estimated mortality rate of approximately 35%, and survivors frequently develop heart failure and arrhythmias, underscoring the need for new therapeutic strategies. Growing evidence indicates that mitochondrial dysfunction in cardiomyocytes (CMCs) is a major driver of post-MI remodeling. Consequently, targeting mitochondrial dynamics and subpopulation-specific responses has emerged as a promising cardioprotective approach. While acute-phase mitochondrial changes after MI have been extensively studied, remodeling during the subacute and chronic stages remains less understood, despite its critical role in scar expansion and the progression of heart failure. In this study, we investigated functional and morphological alterations in distinct mitochondrial subpopulations of left ventricular CMCs two weeks after MI.
Methods:
MI was induced in adult rats by permanent ligation of the left anterior descending coronary artery. Mitochondrial morphology was analyzed by transmission electron microscopy. Mitochondrial function and oxidative stress were assessed in live isolated CMCs using fluorescence and confocal microscopy.
Results:
Two weeks after MI, CMCs exhibited a reduction in total mitochondrial membrane potential (MMP) and an increase in reactive oxygen species levels. Herewith, mitochondrial activity differed among mitochondrial subpopulations. The MMP of perinuclear (PNM) and subsarcolemmal mitochondria (SSM) decreased by ~30% more than that of intermyofibrillar mitochondria (IFM). These functional impairments were accompanied by reductions in mitochondrial size: IFM area decreased by 22%, whereas PNM and SSM decreased by 32% and 29%, respectively. At the same time, mitochondrial volume density decreased in SSM and IFM regions but remained unchanged in PNM regions. Consequently, the overall functional alterations in the PNM regions were comparable to those observed in IFM regions.
Conclusion:
Our data demonstrate a decrease in the activity of CMC mitochondria associated with their fragmentation and reduced volume density two weeks after MI, with the most pronounced changes in SSM. These findings underscore the importance of subpopulation-specific mitochondrial analysis for understanding subacute post-infarction remodeling and for identifying novel therapeutic targets.
