Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺-mediated arrhythmias

New Findings: What is the central question of this study? Knockdown of UCP2 reduces mitochondrial Ca²⁺ uptake. This suggests that Ucp2 knockout mice need to have additional effects on cytosolic Ca²⁺ handling to prevent Ca²⁺ overload. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. What is the main finding and its importance? In Ucp2 knockout mice, decreased mitochondrial Ca²⁺ uptake is compensated for by functional inhibition of L-type Ca²⁺ channels and resultant shortening of action potential duration. UCP2-dependent modulations have a major impact on cardiac electrophysiology, resulting in alterations of ECG characteristics and a higher susceptibility to Ca²⁺-mediated ventricular arrhythmias. Uncoupling protein 2 (mitochondrial, proton carrier) (UCP2) belongs to a superfamily of mitochondrial ion transporters. Owing to its beneficial influence on production of reactive oxygen species, it is suggested to reduce cardiac ischaemia–reperfusion injury. Recent studies have uncovered its ability to regulate mitochondrial Ca²⁺ uptake and therefore to influence cardiac cytosolic Ca²⁺ handling, indicating compensatory pathways to avoid toxic Ca²⁺ overload in Ucp2 knockout (Ucp2^−/−) mice. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. Molecular analyses, whole-cell patch clamp in cardiomyocytes and ECG studies were performed in Ucp2^−/− and wild-type (WT) control mice. Furthermore, to explore the impact on cardiac arrhythmogenicity, ECG monitoring was performed in basal conditions and during Ca²⁺-mediated stress using Bay K 8644. Although cardiac ryanodine receptor 2, NCX1, L-type Ca²⁺ channel (LTCC) and SERCA2a expression were not altered, Ucp2^−/− mice revealed major variations in cardiac electrophysiology. The LTCC current and APD₉₀ were decreased in Ucp2^−/− mice, indicating compensatory mechanisms. Furthermore, in Ucp2^−/− mice, an increased slope factor of action potential upstrokes and more hyperpolarized resting membrane potential were measured, suggesting variations in cardiac excitability. In agreement with alterations of cellular physiology in Ucp2^−/− mice, reductions in PR and QRS as well as shortening of the QTc interval were noted in ECG recordings. Importantly, an increased incidence of cellular after-depolarizations and more pronounced susceptibility to Ca²⁺-mediated arrhythmias were observed. Furthermore, although expression of UCP3 was not different, levels of PRMT1 were significantly higher in Ucp2^−/− mice. Our observations indicate compensatory mechanisms by which Ucp2^−/− mice prevent toxic cytosolic Ca²⁺ overload. UCP2-dependent modulations have a major impact on cardiac electrophysiology and influence susceptibility to Ca²⁺-mediated ventricular arrhythmias.