Cardiac α1‐adrenergic signaling accelerates mitochondrial Ca2+ uptake, ROS generation and cell death signaling through Pyk2‐dependent phosphorylation of the mitochondrial Ca2+ uniporter (893.9)

Abstract

Mitochondrial Ca2+ homeostasis controls the balance of cell survival and death. The molecular identity of the mitochondrial Ca2+ uniporter (MCU) has been just reported and basal tyrosine phosphorylation of MCU was shown in mass spectroscopy of human tissues. However, the physiological and pathophysiological relevance of MCU post‐translational modifications are unknown. Here we reported that α1‐adrenoceptor (α1‐AR) signaling induces mitochondrial Ca2+ overload and reactive oxygen species (ROS) generation and activates cell death signaling through MCU tyrosine phosphorylation in cardiomyocytes. α1‐AR signaling activates mitochondria‐localized proline‐rich tyrosine kinase 2 (Pyk2) and accelerates mitochondrial Ca2+ uptake via Pyk2‐dependent MCU phosphorylation which enhances tetrameric MCU channel pore formation. Moreover, mitochondrial Ca2+‐overload thorough this signaling stimulates mitochondrial superoxide generation, permeability transition pore (mPTP) activity, and initiates apoptotic cell death in adult cardiomyocytes. Thus, α1‐AR‐Pyk2‐MCU signaling may become novel potent therapeutic targets for preventing mitochondrial Ca2+ overload, oxidative stress and cardiac injury under persistent adrenergic stimulation such as during heart failure.