EPAS1 directs a network of genes implicated in mitochondrial dysfunction in arrhythmogenic cardiomyopathy [Spatial Transcriptomics]

Patients diagnosed with arrhythmogenic cardiomyopathy (ACM) often harbor desmosomal mutations, predisposing them to arrhythmia and sudden cardiac death. The molecular mechanisms underlying pathobiology remain incompletely understood, which is reflected by the limited number of therapeutic strategies. Here, we performed spatially resolved transcriptomics on an explanted heart isolated from a patient bearing a mutation in desmoplakin. Exploration of the transcriptional atlas uncovered endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. By combining these data with multiple models of cardiac disease, we show that induced EPAS1 levels activate expression of genes involved in mitophagy and the antioxidant response. Findings were validated in additional explanted heart from ACM and dilated cardiomyopathy patients. Together, genetically impaired cardiomyocytes display mitochondrial dysfunction, consequently resulting in stabilization of EPAS1. In turn, this factor dictates a gene network involved in mitigating the adverse effects of oxidative stress. Overall design: Spatial transcriptomics on an explanted heart collected from an ACM patient bearing a nonsense mutation in DSP.