Mitochondrial Calcium Overload In The Genesis Of Early Afterdepolarizations In Cardiac Myocytes

Early afterdepolarizations (EADs) are secondary depolarizations during the repolarization phase of action potential (AP). EADs are arrhythmogenic events caused by abnormal Ca2+ handling and ion channel malfunctions. A positive feedback loop between intracellular Ca2+ and Ca-dependent ionic currents plays an important role in the genesis of EADs, in which the role of mitochondrial Ca2+ cycling has not been well understood. Ca2+ enters mitochondria through mitochondrial Ca2+ uniporter (MCU) and leaves via Na+/Ca2+/Li+ exchanger (NCLX). Under diseased conditions, this intracellular-mitochondrial interaction is wrecked, resulting in mitochondrial Ca2+ overload. This Ca2+ overload triggers the opening of mitochondrial permeable transitions pores (mPTPs); thus, activating ROS/oxidized Ca2+ /calmodulin-dependent protein kinase II (CaMKII) pathways, which further alter ion channel functions. Here we use spatiotemporal ventricular myocyte models for mouse and rabbit to understand the underlying mechanisms of EADs promoted by mitochondrial Ca2+ overload. We found that; 1) MCU ablation suppresses EADs in the mouse model and enhances EADs in the rabbit model without mitochondrial depolarizations. 2) NCLX overexpression without mitochondria depolarization promotes EADs in both models. 3) Ca2+- dependent opening of mPTP due to upregulation of MCU activity or due to downregulation of NCLX function can either promote or suppress EADs because of the ROS regulation of sarcoplasmic reticulum Ca2+ release and uptake and the oxidized CaMKII signaling pathways. In conclusion, mitochondrial Ca2+ overload with and without mitochondrial depolarizations play a complex role in generating EADs in cardiac myocytes.