ATP synthase subunit alpha and LV mass in ischaemic human hearts

Mitochondrial dysfunction plays a critical role in the development of ischaemic cardiomyopathy (ICM). In this study, the mitochondrial proteome in the cardiac tissue of ICM patients was analysed by quantitative differential electrophoresis (2D-DIGE) and mass spectrometry (MS) for the first time to provide new insights into cardiac dysfunction in this cardiomyopathy. We isolated mitochondria from LV samples of explanted hearts of ICM patients (n = 8) and control donors (n = 8) and used a proteomic approach to investigate the variations in mitochondrial protein expression. We found that most of the altered proteins were involved in cardiac energy metabolism (82%). We focused on ATPA, which is involved in energy production, and dihydrolipoyl dehydrogenase, implicated in substrate utilization, and observed that these molecules were overexpressed and that the changes detected in the processes mediated by these proteins were closely related. Notably, we found that ATPA overexpression was associated with reduction in LV mass (r = -0.74, P < 0.01). We also found a substantial increase in the expression of elongation factor Tu, a molecule implicated in protein synthesis, and PRDX3, involved in the stress response. All of these changes were validated using classical techniques and by using novel and precise selected reaction monitoring analysis and an RNA sequencing approach, with the total heart samples being increased to 24. This study provides key insights that enhance our understanding of the cellular mechanisms related to the pathophysiology of ICM and could lead to the development of aetiology-specific heart failure therapies. ATPA could serve as a molecular target suitable for new therapeutic interventions.