Temporal proteomics maps concealed-stage remodeling and reveals early mitochondrial alteration as an intervention target in a model of PKP2-arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy is a heritable cardiac disorder commonly linked to alterations in desmosomal proteins. While desmosomal dysfunction is a recognized pathogenic mechanism, the early molecular remodeling that precedes clinical manifestations remains unclear. Here we used a mouse model with inducible cardiomyocyte-specific knockout of Pkp2 (encoding plakophilin-2) and performed time-resolved mass spectrometry-based proteomics to map disease progression from early PKP2 loss to structural remodeling. Molecular changes preceded phenotypic abnormalities, and spatial asymmetry was evident, with earlier and more pronounced proteome remodeling in the right ventricle despite comparable PKP2 depletion in both ventricles. Downregulation of protein networks spanning desmosomes, sarcomeres and mitochondria suggests their functional coupling, with mitochondrial remodeling emerging as an early and progressively worsening feature. Intervention with honokiol attenuated changes across the major protein networks, highlighting mitochondrial pathways as promising therapeutic targets and honokiol as a potential strategy to delay arrhythmogenic cardiomyopathy progression. Our findings provide critical insights into the concealed stage of disease progression and identify molecular targets for early intervention. Achter, Svenningsen, Mulvey, Bertoli et al. use an inducible cardiomyocyte-specific Pkp2 knockout model to map the spatiotemporal proteomic changes underlying arrhythmogenic cardiomyopathy. They identify early mitochondrial remodeling preceding overt disease and show that honokiol attenuates pathological protein network alterations.