168 Chapter 7 electron microscopy showed accumulation of lipid droplets and a disrupted morphology of mitochondria in mutant samples compared to controls, indicating insufficient FAO, which might contribute to lipotoxicity, and eventually cardiomyocyte death.171 Successively, a study performed in both PLN-R14del hiPSC-CMs and derived engineered heart tissues (EHTs) showed a lower abundance of mitochondria, perinuclear lipid accumulation, altered post-translational modifications of key metabolic enzymes such as PDH (Pyruvate dehydrogenase) and AMPK (AMP-activated protein kinase), and oxidative stress, as a consequence of ER/mitochondria contact site disruption in mutant samples compared to isogenic controls.172,173 Taken together, these data indicate PLN-R14del-mediated dysfunction of the ER/mitochondria compartment as a novel molecular disease mechanism and a target for future treatments. Figure 4: Metabolic function in PLN wildtype versus PLN-R14del. In healthy cells, cardiomyocytes balance between glucose and fatty acid β-oxidation for energy production. In PLN-R14del, impaired mitochondrial function and stress can occur due to increased reactive oxygen species (ROS), Calcium disruption, mitochondrial impairments, and alterations in the transcriptional regulation of mitochondrial proteins. During mitochondrial stress, energy substrate utilization switches to glycolysis, thereby impairing the FAO and resulting in the accumulation of perinuclear lipids. Fibrosis; localization and the effect of fatty infiltration Cardiac fibrosis is a frequent finding during the histological examination of heart tissues from PLN-R14del patients with end-stage disease.174,175 Significant replacement fibrosis and myofibrillar disarrangement have been first identified in the PLN-R14del patients belonging to the large Greek family with clinical manifestation of DCM and ACM.176 Similar findings have been shown in a transgenic and homozygous PLN-R14del mouse model.160,176 Generally, the
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