PKD Regulates Mitochondrial Morphology and Function via Phosphorylation of DLP1 in Cardiac Myocytes.

Abstract

Regulation of mitochondrial morphology and dynamics is essential for maintaining cardiomyocyte function. Abnormal mitochondrial morphology and mitochondrial dysfunction are frequently observed in both human heart failure (HF) and animal HF models. However, it is still unclear which cardiac signaling pathway(s) regulate(s) mitochondrial morphology/function under pathophysiological conditions. Since Gq‐protein coupled receptor (GqPCR) signaling is critical for the development and progression of HF, we tested the hypothesis that GqPCR stimulation induces pathological changes in mitochondrial morphology/function in cardiomyocytes. We found that protein kinase D (PKD) was activated and translocated to the outer mitochondrial membrane by GqPCR stimulation. GqPCR‐mediated PKD activation induced mitochondrial fragmentation, increased reactive oxygen species generation and mitochondrial permeability transition pore opening followed by caspase‐3 activation. These morphological and functional changes in cardiac mitochondria were mediated via PKD‐dependent phosphorylation of Dynamin‐Like Protein 1 (DLP1) at S637. Importantly, PKD‐dependent DLP1 phosphorylation at S637 concurrent with abnormal mitochondrial morphology and apoptotic signaling were also observed in ventricular tissue from transgenic mice with cardiac‐specific overexpression of constitutively active Gq. In conclusion, we demonstrate that GqPCR stimulation induces mitochondrial fragmentation and dysfunction via PKD‐dependent phosphorylation of DLP1 at S637, which likely contributes to cardiomyocyte dysfunction during HF.