Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism
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Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism. / Loos, Malte; Klampe, Birgit; Schulze, Thomas; Yin, Xiaoke; Theofilatos, Konstantinos; Ulmer, Bärbel Maria; Schulz, Carl; Behrens, Charlotta S; van Bergen, Tessa Diana; Adami, Eleonora; Maatz, Henrike; Schweizer, Michaela; Brodesser, Susanne; Skryabin, Boris V; Rozhdestvensky, Timofey S; Bodbin, Sara; Stathopoulou, Konstantina; Christ, Torsten; Denning, Chris; Hübner, Norbert; Mayr, Manuel; Cuello, Friederike; Eschenhagen, Thomas; Hansen, Arne.
in: STEM CELL REP, Jahrgang 18, Nr. 11, 14.11.2023, S. 2123-2137.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism
AU - Loos, Malte
AU - Klampe, Birgit
AU - Schulze, Thomas
AU - Yin, Xiaoke
AU - Theofilatos, Konstantinos
AU - Ulmer, Bärbel Maria
AU - Schulz, Carl
AU - Behrens, Charlotta S
AU - van Bergen, Tessa Diana
AU - Adami, Eleonora
AU - Maatz, Henrike
AU - Schweizer, Michaela
AU - Brodesser, Susanne
AU - Skryabin, Boris V
AU - Rozhdestvensky, Timofey S
AU - Bodbin, Sara
AU - Stathopoulou, Konstantina
AU - Christ, Torsten
AU - Denning, Chris
AU - Hübner, Norbert
AU - Mayr, Manuel
AU - Cuello, Friederike
AU - Eschenhagen, Thomas
AU - Hansen, Arne
N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2023/11/14
Y1 - 2023/11/14
N2 - Primary carnitine deficiency (PCD) is an autosomal recessive monogenic disorder caused by mutations in SLC22A5. This gene encodes for OCTN2, which transports the essential metabolite carnitine into the cell. PCD patients suffer from muscular weakness and dilated cardiomyopathy. Two OCTN2-defective human induced pluripotent stem cell lines were generated, carrying a full OCTN2 knockout and a homozygous OCTN2 (N32S) loss-of-function mutation. OCTN2-defective genotypes showed lower force development and resting length in engineered heart tissue format compared with isogenic control. Force was sensitive to fatty acid-based media and associated with lipid accumulation, mitochondrial alteration, higher glucose uptake, and metabolic remodeling, replicating findings in animal models. The concordant results of OCTN2 (N32S) and -knockout emphasizes the relevance of OCTN2 for these findings. Importantly, genome-wide analysis and pharmacological inhibitor experiments identified ferroptosis, an iron- and lipid-dependent cell death pathway associated with fibroblast activation as a novel PCD cardiomyopathy disease mechanism.
AB - Primary carnitine deficiency (PCD) is an autosomal recessive monogenic disorder caused by mutations in SLC22A5. This gene encodes for OCTN2, which transports the essential metabolite carnitine into the cell. PCD patients suffer from muscular weakness and dilated cardiomyopathy. Two OCTN2-defective human induced pluripotent stem cell lines were generated, carrying a full OCTN2 knockout and a homozygous OCTN2 (N32S) loss-of-function mutation. OCTN2-defective genotypes showed lower force development and resting length in engineered heart tissue format compared with isogenic control. Force was sensitive to fatty acid-based media and associated with lipid accumulation, mitochondrial alteration, higher glucose uptake, and metabolic remodeling, replicating findings in animal models. The concordant results of OCTN2 (N32S) and -knockout emphasizes the relevance of OCTN2 for these findings. Importantly, genome-wide analysis and pharmacological inhibitor experiments identified ferroptosis, an iron- and lipid-dependent cell death pathway associated with fibroblast activation as a novel PCD cardiomyopathy disease mechanism.
KW - Animals
KW - Humans
KW - Organic Cation Transport Proteins/genetics
KW - Solute Carrier Family 22 Member 5/genetics
KW - Ferroptosis
KW - Induced Pluripotent Stem Cells
KW - Cardiomyopathies/genetics
KW - Lipids
U2 - 10.1016/j.stemcr.2023.09.002
DO - 10.1016/j.stemcr.2023.09.002
M3 - SCORING: Journal article
C2 - 37802072
VL - 18
SP - 2123
EP - 2137
JO - STEM CELL REP
JF - STEM CELL REP
SN - 2213-6711
IS - 11
ER -