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Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation

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Item Type:Article
Title:Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation
Creators Name:Cuello, F. and Knaust, A.E. and Saleem, U. and Loos, M. and Raabe, J. and Mosqueira, D. and Laufer, S. and Schweizer, M. and Kraak, P. and Flenner, F. and Ulmer, B.M and Braren, I. and Yin, X. and Theofilatos, K. and Ruiz-Orera, J. and Patone, G. and Klampe, B. and Schulze, T. and Piasecki, A. and Pinto, Y. and Vink, A. and Hübner, N. and Harding, S. and Mayr, M. and Denning, C. and Eschenhagen, T. and Hansen, A.
Abstract:The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca(2+) transient decay time, Ca(2+)‐load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow‐up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end‐stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non‐failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca(2+)‐binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca(2+)‐scavenging, suggesting impaired local Ca(2+) cycling as an important disease culprit.
Keywords:Endoplasmic Reticulum, Engineered Heart Tissue, Human-Induced Pluripotent Stem Cells, Mitochondria, Phospholamban p.Arg14del
Source:EMBO Molecular Medicine
ISSN:1757-4676
Publisher:Wiley
Volume:13
Number:6
Page Range:e13074
Date:7 June 2021
Official Publication:https://doi.org/10.15252/emmm.202013074
PubMed:View item in PubMed

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