Junctophilin-2 Regulates Mitochondrial Metabolism

Abstract

Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function as Jph2 knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.

Altered myocardial lipid regulation in junctophilin-2–associated familial cardiomyopathies

“…Our study focused on two types of inherited cardiomyopathy, HCM and DCM, caused by inherited variants in the JPH2 gene ( Quick et al, 2017 ; Jones et al, 2019 ). JPH2 is a structural protein that connects the PM to intracellular organelles such as the ER/SR and likely also the mitochondria ( Garbino et al, 2009 ; Beavers et al, 2014 ; Prisco et al, 2023 Preprint ). Inherited JPH2 variants associated with HCM cause aberrant transverse tubule organization and deficits in intracellular Ca 2+ handling ( Quick et al, 2017 ).…”

“…Palmitoylation of JPH2 enables binding to lipid raft domains in the PM ( Jiang et al, 2019 ). Moreover, Prisco et al (2023 Preprint ) recently showed that fatty acid oxidation is impaired in human induced pluripotent stem cell–derived cardiomyocytes in which JPH2 was ablated. A recent lipidomic study of surgical myectomy specimens from an HCM patient with symptomatic left ventricular outflow tract obstruction revealed accumulation of free fatty acids, whereas the concentrations of acylcarnitines and free carnitine were markedly reduced ( Ranjbarvaziri et al, 2021 ).…”