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

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.

Citation

Loos, M., Klampe, B., Schulze, T., Yin, X., Theofilatos, K., Ulmer, B. M., …Hansen, A. (2023). Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism. Stem Cell Reports, 18(11), 2123-2137. https://doi.org/10.1016/j.stemcr.2023.09.002

• Journal Article Type: Article
• Acceptance Date: Sep 4, 2023
• Online Publication Date: Sep 19, 2023
• Publication Date: Nov 14, 2023
• Deposit Date: Nov 21, 2023
• Publicly Available Date: Nov 22, 2023
• Journal: Stem Cell Reports
• Electronic ISSN: 2213-6711
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 18
• Issue: 11
• Pages: 2123-2137
• DOI: https://doi.org/10.1016/j.stemcr.2023.09.002
• Keywords: Dilated Cardiomyopathy, iPSC, disease modeling, Metabolism, Cardiomyocytes
• Public URL: https://nottingham-repository.worktribe.com/output/26519611
• Publisher URL: https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(23)00361-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2213671123003612%3Fshowall%3Dtrue
• Additional Information: This article is maintained by: Elsevier; Article Title: Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism; Journal Title: Stem Cell Reports; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.stemcr.2023.09.002; Content Type: article; Copyright: © 2023 The Author(s).