367 General Discussion - hiPSC-CMs Disease Modelling and Future Perspectives 13 Figure 4. Overview of the potential pathological mechanisms leading to PLN-R14del induced heart failure. Right panels display the initial molecular mechanisms and the effect of the PLN-R14del on the PLN conformation leading to a reduced SERCA activity, increased cytosolic calcium, increased mitochondrial damage and glycolysis, and misfolded PLN-R14del leading to increased UPR and protein aggregation. Left panels describe the secondary effect of the mutation, with cardiomyocyte dysfunction and fibrosis, leading to an ACM and/or DCM phenotype in the PLN-R14del patient. Abbreviations: TCA; The tricarboxylic acid cycle, FAO; Fatty acid oxidation pathway, PKA; protein kinase A. ACM; Arrhythmogenic cardiomyopathy, DCM; Dilated cardiomyopathy. Created with BioRender.com. 3) The Ca2+ overload may increase the Ca2+ in different structures (e.g. SR, cytoplasm, and mitochondria) to an excessive level, which induces electrical and mechanical abnormalities such as arrhythmias and a decrease in the force of contraction. 4) Additionally, toxic levels of Ca2+ in the ER can severely impact folding capacity. The toxic increase of mitochondrial Ca2+ leads to altered metabolism and increased production of ROS, triggering cell death. Intracellular Ca2+ activates the calcineurin/NFAT, ERK1/2, ROS/RhoA, and sFRP2 pathways to promote profibrotic gene expression.100 For the last 3 pathologic observations, however, it remains unknown which pathway fails first, triggering the others to fail as well, or if all events happen at the same time. For example, high UPR activation in the CM could cause mitochondrial UPR activation and trigger mitochondrial damage, or the increased mitochondrial Ca2+ concentration triggers mitochondrial damage, thereby activating the UPR. Additionally, the activation of profibrotic pathways could also be caused by cardiomyocyte apoptosis, rather than elevated intracellular Ca2+ levels. Finally, since the PLN-R14del
RkJQdWJsaXNoZXIy MTk4NDMw