Open AccessImpairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation
Author(s) -
Cuello Friederike,
Knaust Anika E,
Saleem Umber,
Loos Malte,
Raabe Janice,
Mosqueira Diogo,
Laufer Sandra,
Schweizer Michaela,
Kraak Petra,
Flenner Frederik,
Ulmer Bärbel M,
Braren Ingke,
Yin Xiaoke,
Theofilatos Konstantinos,
RuizOrera Jorge,
Patone Giannino,
Klampe Birgit,
Schulze Thomas,
Piasecki Angelika,
Pinto Yigal,
Vink Aryan,
Hübner Norbert,
Harding Sian,
Mayr Manuel,
Denning Chris,
Eschenhagen Thomas,
Hansen Arne
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013074
Subject(s) - german , medicine , library science , history , computer science , archaeology
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.