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. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant ( Dsg2 mut/mut ) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis 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 (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2 mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), 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.