Cardiac stress responses in Marfan syndrome may activate mechanisms related to mitochondrial dysfunction: analyses in human stem cell-derived cardiomyocytes
Le résumé fourni par la source
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic FBN1 variants, affecting the extracellular matrix (ECM) protein fibrillin-1. Besides aortic pathology, several patients show myocardial dysfunction, suggesting cardiomyopathy may be an intrinsic feature of MFS. Fibrillin sequesters latent TGF-β complexes in the ECM, with ECM disruption increasing TGF-β signalling and driving remodelling. Cardiomyocytes are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for ATP production, calcium homeostasis, and contractile function. Because FBN1 mutations disrupt ECM integrity and enhance TGF-β signalling, the resulting ECM-driven alterations may affect cardiomyocyte mitochondrial function. Such mitochondrial dysfunction can impair energy metabolism and electrical stability, favouring arrhythmogenesis. This project investigates the impact of FBN1 mutations on mitochondrial function in cardiomyocytes, by studying metabolic and structural alterations in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from MFS patient cells. Three cell lines carrying distinct pathogenic FBN1 variants and CRISPR-corrected isogenic controls are included. Mitochondrial respiration was assessed using Seahorse XF analysis, measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Immunofluorescence staining evaluated cardiomyocyte identity and fibrillin distribution both intracellularly and in the ECM using antibodies against α-actinin, connexin 43, and fibrillin. Spontaneous electrical activity and ultrastructural mitochondrial morphology was measured by Multi-Electrode Array (MEA) and Transmission Electron Microscopy (TEM) respectively. These experiments were performed using optimised methods, and preliminary results will be presented.
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