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| Item Type: | Article |
|---|---|
| Title: | Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism |
| Creators Name: | Loos, M. and Klampe, B. and Schulze, T. and Yin, X. and Theofilatos, K. and Ulmer, B.M. and Schulz, C. and Behrens, C.S. and van Bergen, T.D. and Adami, E. and Maatz, H. and Schweizer, M. and Brodesser, S. and Skryabin, B.V. and Rozhdestvensky, T.S. and Bodbin, S. and Stathopoulou, K. and Christ, T. and Denning, C. and Hübner, N. and Mayr, M. and Cuello, F. and Eschenhagen, T. and Hansen, A. |
| 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: | Disease Modeling, Metabolism, Dilated Cardiomyopathy, iPSC, Cardiomyocytes, Animals |
| Source: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 18 |
| Number: | 11 |
| Page Range: | 2123-2137 |
| Date: | 14 November 2023 |
| Official Publication: | https://doi.org/10.1016/j.stemcr.2023.09.002 |
| PubMed: | View item in PubMed |
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