PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1α-dependent mechanism

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease in which most patients carry (likely) pathogenic variants in desmosomal genes, most commonly in plakophilin-2 (PKP2). While the genetic causes are well described, the molecular mechanisms driving disease progression—particularly in response to exercise—remain poorly understood.

To investigate disease-driving pathways in ACM, we used PKP2 mutant human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from ACM patients. Transcriptomic profiling revealed consistent downregulation of oxidative phosphorylation (OXPHOS) genes in PKP2 mutant hiPSC-CMs, which was confirmed in explanted ACM hearts carrying PKP2 variants. Reduced expression of OXPHOS-related genes was associated with lower PPARGC1A expression and decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. The reduction in PPARGC1A expression appeared to result, at least in part, from decreased AMPKα protein levels, a known activator of PPARGC1A previously shown to localize at the intercalated disc, as PKP2 mutant cells failed to increase PPARGC1A expression following treatment with AICAR, an AMPK activator. To directly assess whether increasing PPARGC1A expression could compensate for this defect, we overexpressed PPARGC1A, which partially restored OXPHOS gene expression and improved contractility in PKP2 mutant cells.

Our study identifies a novel transcriptional mechanism linking PKP2 loss to reduced mitochondrial function via decreased PGC1α signaling, partially through reduced AMPKα levels. Disruption of this axis reduces OXPHOS gene expression and mitochondrial function in PKP2 mutant hiPSC-CMs, potentially impairing the heart’s ability to meet increased energy demands during stress, and offering a mechanistic explanation for the detrimental effects of exercise in ACM. Furthermore, these findings highlight PGC1α induction as a potential therapeutic strategy to restore OXPHOS gene expression and mitochondrial adaptability in ACM.