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

Abstract

BACKGROUND. Takotsubo syndrome (TTS) is characterized by transient contractile dysfunction with its mechanism undefined. We showed that activation of cardiac Hippo pathway mediates mitochondrial dysfunction, and that stimulation of β-adrenoceptors (βAR) activates Hippo pathway. Here we investigated the role of βAR-Hippo signaling in mediating mitochondrial dysfunction in isoproterenol-induced TTS-like mouse model. METHODS. Elderly post-menopausal female mice were administered with isoproterenol (1.25 mg/kg/h for 23 hours). Cardiac function was determined by serially echocardiography. At day-1 and day-7 post-isoproterenol 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. RESULTS. Isoproterenol exposure induced transient increase in biomarkers of cardiac damage, and ventricular contractile dysfunction and dilation. At day-1 post-isoproterenol, 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 ROS. All changes were reversed by day-7. βAR 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. CONCLUSION. Stimulation of cardiac βAR activates Hippo pathway that mediates mitochondrial dysfunction with energy insufficiency and enhanced ROS, promoting acute but transient ventricular dysfunction.

TEAD1, MYO7A and NDUFC2 are novel functional genes associated with glucose metabolism in BXD recombinant inbred population

“…Furthermore, in vivo experiments have shown a decrease in glucose‐related phenotypes in the TEAD1 KO mice (Figure 3G‐I), while siRNA‐mediated knockdown of TEAD1 resulted in the downregulation of genes associated with insulin signalling and glucose metabolism pathways (Figure 6A) and reduced glucose uptake in vitro (Figure 6D). This was consistent with previous findings, that is enhanced transcriptional activity of TEAD1 and the YAP/TEAD1 complex increased glucose uptake and lactate, and ATP production 52 . Furthermore, it has been reported that TEAD1 directly maintains the expression of nuclear DNA‐encoded mitochondrial genes required for ATP synthesis 53–55 .…”

“…This was consistent with previous findings, that is enhanced transcriptional activity of TEAD1 and the YAP/TEAD1 complex increased glucose uptake and lactate, and ATP production. 52 Furthermore, it has been reported that TEAD1 directly maintains the expression of nuclear DNA-encoded mitochondrial genes required for ATP synthesis. [53][54][55] In the current study, we observed that TEAD1 had a significant positive correlation with the genes that regulate mitochondrial function, such as PPARG and GCK (Figure 6A).…”

Animal models of Takotsubo syndrome: bridging the gap to the human condition

“…The reason why approximately 80% of reported cases occur in postmenopausal women is unkown ( 25 ). While studies have been published on the effect of stress and hormonal status on cardiac function ( 76 – 78 ), they have not addressed the crucial features of TS. We would like to emphasize further that being a postmenopausal woman is a characteristic feature of TS, rather than a general trait applicable to all woman.…”

The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress

“…Previous studies have shown that Mst1/2 are activated by various cellular stresses, such as oxidative stress, DNA damage, and neurotoxic stress, and participate in the cellular response to various stressors through noncanonical processes 18 – 21 . Recent studies have also implicated Mst1/2 in mitochondrial functions, including mitochondrial dynamics 22 , 23 . However, the role of Mst1/2 in mitophagy under conditions of mitochondrial stress has not been determined.…”