Desmoglein-2 deficiency drives mitochondrial morphological remodeling in cardiomyocytes.

Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. In addition, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we used a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Reanalysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochondrial abundance than the left ventricle, indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.NEW & NOTEWORTHY This study identified mitochondrial remodeling as a key feature of desmoglein-2 (DSG2)-linked ACM. Using Dsg2mut/mut mice, we showed that DSG2 loss broadly suppresses mitochondrial transcripts involved in fusion/fission, Ca2+ handling, mitophagy, organization, and electron transport chain assembly. Ultrastructural analyses revealed increased mitochondrial abundance, smaller and irregular mitochondrial morphology, and chamber-specific remodeling, with greater RV susceptibility. These findings support a desmosomal-mitochondrial axis and highlight mitochondrial pathways as potential therapeutic targets.