Novel Mitochondrial Ca2+ Uptake Enhancers for the Treatment of Cardiac Arrhythmia

Abstract

Pharmacological activation of mitochondrial Ca2+ uptake is a promising strategy as a novel treatment for Ca2+-triggered cardiac arrhythmias. Though two mitochondrial Ca2+ uptake enhancers (MiCUPs), kaempferol and efsevin, suppressed cardiac arrhythmia in experimental cardiac arrhythmia models, both have significant deficits regarding their druggability. With the aim to find MiCUps with higher affinity to the mitochondrial Ca2+ uptake complex we performed a HeLa cell based high-throughput screen designed to identify substances which enhance mitochondrial Ca2+ uptake. We identified two FDA-approved drugs, which were further investigated for their efficacy in cardiac model systems. In HL-1 cardiomyocytes both increased SR-mitochondria Ca2+ transfer with a significantly lower EC50 compared to efsevin or kaempferol, while SR Ca2+ release remained unaffected. To investigate the anti-arrhythmogenic potential of these two compounds, we tested them in two model systems for Ca2+-triggered arrhythmias. In freshly isolated cardiomyocytes from a murine model for catecholaminergic polymorphic ventricular tachycardia (CPVT, RyRR4496C/WT mouse) both novel MiCUps efficiently blocked spontaneous diastolic Ca2+ waves and secondary systolic Ca2+ elevations, two cellular mechanisms of arrhythmogenesis. Strikingly these effects were abolished in RyRR4496C/WT cardiomyocytes from a MCU-/- background, indicating a causative link between the enhanced mitochondrial Ca2+ uptake and the antiarrhythmic effects of the two novel MiCUps. To test their translational potential we tested both substances in iPSC-derived cardiomyocytes from a CPVT patient and found that they likewise reduce arrhythmogenic events. Finally in a zebrafish in vivo model for Ca2+ overload induced cardiac fibrillation (NCX-null) both novel MiCUps restored coordinated contractions in otherwise fibrillating embryonic hearts. This study underlines the important role of mitochondria for the regulation of cardiac Ca2+ handling and the therapeutic potential of MiCUps as pharmacological agents for the treatment of cardiac arrhythmia.