Abstract
Background: Arrhythmogenic Cardiomyopathy (ACM) is a cardiac disease characterized by a progressive replacement of the myocardium with fibro-fatty tissue. ACM can be associated with stressful-life-threatening arrhythmias, eventually leading to sudden cardiac death. Despite genetic predisposition being the main underlaying cause of ACM, the genetic background alone cannot fully explain disease severity and penetrance. Emerging evidence suggests an active role of mitochondria and ROS) signaling in ACM pathogenesis (Lippi et al. 2023, Volani et al. 2022, van Opbergen et al. 2019). Thus, the current project employs primary Cardiac Stromal Cells (CStC) from several ACM patients to explore whether mitochondrial fitness and redox systems are altered and how they can be linked to disease etiology and progression.
Material and Methods: CStCs were cultured either in basal medium (BM) or adipogenic medium (AM), a condition used to model the ACM fibro-fatty phenotype. Mitochondria-related analyses of ultrastructure, membrane potential, network connection, respiratory capacity, ROS production and redox system were performed at day (d) 0 in BM and at d3, d7, d15 of AM exposure.
Results and Discussion: Mitochondria appear visually healthy in ACM both in BM, with no difference in mitochondrial membrane potential, fusion/fission mechanisms, mitochondrial density, and ETC protein expression. Despite that, the mitochondrial network is more fragmented in ACM compared to healthy CStCs (CTR) in BM, which goes along with a decreased mitochondrial respiratory capacity and increased ROS production. Interestingly, we observed mitochondrial and cellular remodeling on d3 of AM and a significant increase of mitochondrial respiratory capacity in ACM compared to CTR cells at d7 of AM.
Conclusion: This study performs a comprehensive analysis of mitochondrial morphology, dynamics, function, and redox status in CStCs from ACM subjects carrying different genetic backgrounds to provide evidence for mitochondrial changes as co-factors in ACM progression.
Funding Sources: This research was funded by the Joint Project Südtirol- FWF (grant number 23623; Italy-Austria) and the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol (Italy).