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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, Vol. 18, No. 11, 14.11.2023, p. 2123-2137.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Loos, M, Klampe, B, Schulze, T, Yin, X, Theofilatos, K, Ulmer, BM, Schulz, C, Behrens, CS, van Bergen, TD, Adami, E, Maatz, H, Schweizer, M, Brodesser, S, Skryabin, BV, Rozhdestvensky, TS, Bodbin, S, Stathopoulou, K, Christ, T, Denning, C, Hübner, N, Mayr, M, Cuello, F, Eschenhagen, T & Hansen, A 2023, 'Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism', STEM CELL REP, vol. 18, no. 11, pp. 2123-2137. https://doi.org/10.1016/j.stemcr.2023.09.002

APA

Loos, M., Klampe, B., Schulze, T., Yin, X., Theofilatos, K., Ulmer, B. M., Schulz, C., Behrens, C. S., van Bergen, T. D., Adami, E., Maatz, H., Schweizer, M., Brodesser, S., Skryabin, B. V., Rozhdestvensky, T. S., Bodbin, S., Stathopoulou, K., Christ, T., Denning, C., ... Hansen, A. (2023). Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism. STEM CELL REP, 18(11), 2123-2137. https://doi.org/10.1016/j.stemcr.2023.09.002

Vancouver

Loos M, Klampe B, Schulze T, Yin X, Theofilatos K, Ulmer BM et al. Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism. STEM CELL REP. 2023 Nov 14;18(11):2123-2137. https://doi.org/10.1016/j.stemcr.2023.09.002

Bibtex

@article{31574fd43ff84b51b7d31a1051c6832a,
title = "Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism",
abstract = "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.",
keywords = "Animals, Humans, Organic Cation Transport Proteins/genetics, Solute Carrier Family 22 Member 5/genetics, Ferroptosis, Induced Pluripotent Stem Cells, Cardiomyopathies/genetics, Lipids",
author = "Malte Loos and Birgit Klampe and Thomas Schulze and Xiaoke Yin and Konstantinos Theofilatos and Ulmer, {B{\"a}rbel Maria} and Carl Schulz and Behrens, {Charlotta S} and {van Bergen}, {Tessa Diana} and Eleonora Adami and Henrike Maatz and Michaela Schweizer and Susanne Brodesser and Skryabin, {Boris V} and Rozhdestvensky, {Timofey S} and Sara Bodbin and Konstantina Stathopoulou and Torsten Christ and Chris Denning and Norbert H{\"u}bner and Manuel Mayr and Friederike Cuello and Thomas Eschenhagen and Arne Hansen",
note = "Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2023",
month = nov,
day = "14",
doi = "10.1016/j.stemcr.2023.09.002",
language = "English",
volume = "18",
pages = "2123--2137",
journal = "STEM CELL REP",
issn = "2213-6711",
publisher = "Cell Press",
number = "11",

}

RIS

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 -