167 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 Figure 3: Protein Toxicity and Unfolded Protein Response in PLN-R14del. In PLN-R14del, the misfolded PLN-R14del protein, calcium disruption, and oxidative stress can lead to increased ER stress. Increased ER stress can lead to higher protein folding toxicity and the activation of the UPR and autophagy proteins LC3 and P62. If the autophagy system is not able to remove all the mutant PLN protein, this results in the accumulation of p62-positive proteotoxic perinuclear aggregates in the cardiomyocytes, which cause cardiomyocyte stress and ultimately induce cell death. Mitochondrial disruption and reduced fatty acid oxidation. Given the unrelenting contraction, cardiomyocytes rely on mitochondria for continuous ATP production. Fuel utilization and energy production are crucial and contribute to the balance between glucose and fatty acid oxidation (FAO). Impaired mitochondrial function in the failing heart can occur due to several reasons, including increased reactive oxygen species (ROS), dysregulation of Ca2+ homeostasis, impairment of mitochondrial dynamics, and alterations in transcriptional regulation of mitochondrial proteins, which lead to a reduced mitochondrial oxidative metabolism and ATP production.169 A recent non-peer-reviewed study analyzed the transcriptional regulation profiling in end-stage hearts from PLN-R14del patients and healthy donors, using multi-omics approaches. They identified differentially acetylated promoters and enhancers (H3K27ac ChIPseq), annotated enriched transcription factor (TF) binding motifs located in those regions, and differentially expressed genes (RNA-seq).170 By integrating the information at the DNA and RNA levels, they detected the downregulation of key TF regulators in FAO metabolism and their downstream target in PLN-R14del hearts as compared to controls. In addition, histological analysis, immunofluorescence staining, and transmission
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