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Takotsubo syndrome TTS is characterized by short-term contractile dysfunction with its mechanism undefined We showed that activation of cardiac Hippo pathway mediates mitochondrial dysfunction and that stimulation of -adrenoceptors AR activates Hippo pathway Here we investigated the role of AR-Hippo signaling in mediating mitochondrial dysfunction in isoproterenol Iso -induced TTS-like mouse model Elderly postmenopausal female mice were administered with Iso 1 25 mg kg h for 23 h Cardiac function was determined by serially echocardiography At days 1 and 7 post-Iso exposure mitochondrial ultrastructure and function were examined by electron microscopy and various assays Alterations in cardiac Hippo pathway and effects of genetic inactivation of Hippo kinase Mst1 on mitochondrial damage and dysfunction in the acute phase of TTS were investigated Isoproterenol exposure induced acute increase in biomarkers of cardiac damage and ventricular contractile dysfunction and dilation At day 1 post-Iso we observed extensive abnormalities in mitochondrial ultrastructure downregulation of mitochondrial marker proteins and mitochondrial dysfunction evidenced by lower ATP content increased lipid droplets higher contents of lactate and augmented reactive oxygen species ROS All changes were reversed by day 7 AR stimulation led to activation of cardiac Hippo pathway with enhanced expression of Hippo kinase Mst1 and inhibitory YAP phosphorylation as well as reduced nuclear YAP-TEAD1 interaction In mice with cardiac expression of inactive mutant Mst1 gene acute mitochondrial damage and dysfunction were mitigated Stimulation of cardiac AR activates Hippo pathway that mediates mitochondrial dysfunction with energy insufficiency and enhanced ROS promoting acute but short-term ventricular dysfunction NEW NOTEWORTHY Takotsubo syndrome TTS is featured by activation of sympatho- -adrenoceptor AR system leading to acute loss of ventricular contractile performance However the molecular mechanism remains undefined We demonstrated in an isoproterenol-induced murine TTS-like model extensive mitochondrial damage metabolic dysfunction and downregulated mitochondrial marker proteins changes temporarily associated with cardiac dysfunction Mechanistically stimulation of AR activated Hippo signaling pathway and genetic inactivation of Mst1 kinase ameliorated mitochondrial damage and metabolic dysfunction at the acute phase of TTS

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Mitochondrial damage in a Takotsubo syndrome-like mouse model mediated by activation of β-adrenoceptor-Hippo signaling p...

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with mammalian sterile 20-like kinase as keyword