التفاصيل البيبلوغرافية
| العنوان: |
Depressed mitochondrial function in cardiomyopathy caused by LMNA gene mutation highlighted in patient-derived iPSC-CMs. |
| المؤلفون: |
Seguret, Magali, Jouve, Charlène, Deshayes, Lucille, Pereira, Céline, Ruiz-Velasco, Andrea, Al Sayed, Zeina R., Wahbi, Karim, Muchir, Antoine, Bonne, Gisèle, Hulot, Jean-Sébastien |
| المصدر: |
Archives of Cardiovascular Diseases; 2024 Supplement, Vol. 117, pS211-S212, 2p |
| مستخلص: |
Mutations in LMNA gene, which encodes lamins A/C, cause a variety of diseases, called laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy. The genotype-phenotype relationship for these mutations is still unclear and there is currently no mutation-specific therapy. Here, we focused on a mutation in the LMNA gene (c.665A>C, p.His222Pro), associated with the Emery-Dreyfuss Muscular dystrophy. We used LMNA H222P mutant induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 corrected isogenic control iPSCs to better characterize the cardiac phenotype associated with the mutation. LMNA H222P mutant and the isogenic control iPSCs clones were differentiated into cardiomyocytes (iPSC-CMs). Ring-shaped cardiac organoids were generated to compare the contractile properties of the two clones. Calcium transients in mutant and corrected iPSC-CMs were measured by live confocal imaging. Basal and maximal mitochondrial respiration were measured by Seahorse. iPSC-CMs were generated from the LMNA mutant and the corrected iPSCs with no difference in the differentiation yield nor in the iPSC-CMs structure. However, cardiac organoids generated with LMNA H222P iPSC-CMs showed an impaired contractility compared to control organoids. Calcium transient recordings in LMNA H222P mutant cardiomyocytes showed a significantly higher calcium transient amplitude with a significantly slower calcium re-uptake. Transcriptomic analyses suggested a global mitochondrial dysfunction and in particular an impaired mitochondrial calcium uptake with a significantly decreased expression of the mitochondrial calcium uniporter (MCU). This decrease in MCU expression was confirmed by Western blot and was accompanied by an increased MICU1: MCU ratio, as well as an increased PDH Ser232 phosphorylation, indicating a decreased mitochondrial calcium uptake in the LMNA mutant iPSC-CMs. Measurement of mitochondrial respiration using Seahorse showed lower basal and maximal respiration in LMNA H222P iPSC-CMs. LMNA H222P mutant iPSC-CMs exhibit contractile dysfunction associated with mitochondrial dysfunction with impaired MCU complex activity, decreased mitochondrial calcium homeostasis and reduced mitochondrial energy production. [ABSTRACT FROM AUTHOR] |
|
Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Supplemental Index |
Full Text via ClinicalKey 
Full Text Finder