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

ABSTRACT Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease where the majority of ACM patients carry a (likely) pathogenic variant in desmosomal genes, predominantly in plakophilin-2 (PKP2). While the genetic cause of the disease is well studied, the molecular disease-driving mechanisms and how exercise can drive disease progression remain poorly understood. In this study, we identified the oxidative phosphorylation (OXPHOS) pathway to be downregulated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and human explanted hearts carrying pathogenic PKP2 variants. The reduced expression of OXPHOS related genes was a result of lower PPARGC1A expression which led to decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. Induction of PPARGC1A expression partially restored the expression of OXPHOS components and improved contractility in PKP2 mutant cells. These results suggest that improving oxidative capacity through modulation of PPARGC1A in cardiomyocytes could be considered as a new therapeutic target for ACM patients in the future. Competing Interest Statement E.v.R. and H.T. are partially employed by Phlox Therapeutics. A.S.J.M.t.R. is a consultant for Tenaya Therapeutics, Rocket Pharmaceuticals, LEXEO and Bristol Meyers Squibb. M.G. serves as a medical advisor for Octovasc, a company developing the Octocon coronary connector, and is listed on related patent applications. She has also received, on behalf of her department, teaching fees from Abbott. These activities are unrelated to the current study. All other authors declare that they have no competing interests.