State of mitochondria in a DSP-linked arrhythmogenic cardiomyopathy: insights from the DspS311A knock-in mouse model

This thesis investigates the contribution of mitochondrial dysfunction to the pathogenesis of arrhythmogenic cardiomyopathy (ACM), with particular emphasis on desmoplakin (DSP)-related cardiomyopathy. ACM is a genetic heart disease characterized by ventricular arrhythmias, fibrofatty myocardial replacement, and progressive heart failure. Although DSP mutations are a well-recognized cause of ACM, the mechanistic links between desmosomal disruption, mitochondrial dysfunction, and disease progression remain poorly defined. To address this gap, we employed a heterozygous DSP knock-in (WT/S311A) murine model and healthy controls. We combined molecular biology, histological analyses, and biochemical assays to assess mitochondrial calcium dynamics, inflammatory signalling, and downstream consequences such as oxidative stress and apoptosis. Our results demonstrate that DSP mutations lead to unbalanced mitochondrial calcium handling accompanied by altered mitochondrial dynamics, including changes in morphology and structural integrity. These defects promoted mitochondrial stress, reactive oxygen species (ROS) generation, and cytochrome c release. In parallel, enhanced inflammatory responses and tissue remodelling were observed, providing evidence for a convergence of calcium dysregulation, disrupted mitochondrial dynamics, and inflammation in ACM. This work establishes mitochondria as key mediators of pathogenesis in DSP cardiomyopathy. By linking desmosomal mutations to mitochondrial and inflammatory pathways, the study contributes to a deeper mechanistic understanding of ACM and highlights mitochondria as potential therapeutic targets in DSP-related cardiac disease.