TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes

Abstract

The Hippo signaling effector, TEAD1 plays an essential role in cardiovascular development. However, a role for TEAD1 in postmitotic cardiomyocytes (CMs) remains incompletely understood. Herein we reported that TEAD1 is required for postmitotic CM survival. We found that adult mice with ubiquitous or CM-specific loss of Tead1 present with a rapid lethality due to an acute-onset dilated cardiomyopathy. Surprisingly, deletion of Tead1 activated the necroptotic pathway and induced massive cardiomyocyte necroptosis, but not apoptosis. In contrast to apoptosis, necroptosis is a proinflammatory form of cell death and consistent with this, dramatically higher levels of markers of activated macrophages and pro-inflammatory cytokines were observed in the hearts of Tead1 knockout mice. Blocking necroptosis by administration of necrostatin-1 rescued Tead1 deletion-induced heart failure. Mechanistically, genome-wide transcriptome and ChIP-seq analysis revealed that in adult hearts, Tead1 directly activates a large set of nuclear DNA-encoded mitochondrial genes required for assembly of the electron transfer complex and the production of ATP. Loss of Tead1 expression in adult CMs increased mitochondrial reactive oxygen species, disrupted the structure of mitochondria, reduced complex I-IV driven oxygen consumption and ATP levels, resulting in the activation of necroptosis. This study identifies an unexpected paradigm in which TEAD1 is essential for postmitotic CM survival by maintaining the expression of nuclear DNA-encoded mitochondrial genes required for ATP synthesis.

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice

“…This indicates a pivotal role of Hippo/YAP/TEAD1 signaling in the onset of DCM. In keeping with recent reports in TEAD1-cKO mice showing suppressed mitochondrial genes and metabolic dysfunction 16 - 18 , we showed in Mst1-TG hearts a lower nYAP/cYAP ratio together with a reduced physical interaction of nuclear YAP/TAZ and TEAD1, albeit a higher YAP abundance likely due to a compensation to YAP inactivation following Mst1 overexpression. The pivotal role of YAP inactivation in mediating dysregulation of mitochondrial genes was confirmed by our finding, in H9c2 cells, of downregulated mitochondrial marker proteins following YAP gene knockdown.…”

“…Indeed, contractile dysfunction of LV and RV was the main abnormality by echocardiography in young TG mice, very likely secondary to mitochondrial dysfunction. Our findings from the 3-wk TG model is in keeping with published studies, showing that inducible gene knockout of YAP or TEAD1 leads to onset of DCM within a few weeks 12 , 15 , 16 , 18 , and that TEAD1-KO results in profound mitochondrial dysfunction 16 , 17 . Collectively, Hippo activation (e.g.…”

“…TEADs, YAP acts either as a transcriptional co-activator or co-repressor 9 , 40 , 41 . Studies in YAP-cKO or TEAD1-cKO models showed onset of DCM phenotype within a few weeks after gene deletion 12 , 15 , 16 , 18 , a pattern similar to that seen in the Mst1-TG model. This indicates a pivotal role of Hippo/YAP/TEAD1 signaling in the onset of DCM.…”

“…Collectively, Hippo activation (e.g. Mst1-TG) or YAP/TEAD1 inactivation mediates cardiac mitochondrial dysfunction 16 , 17 , that constitutes a causal mechanism in de novo onset of DCM. Recent studies implicated regulation by the Hippo pathway of fibrosis signaling 7 , 12 , 13 , 15 , 40 , 41 .…”

“…We noticed in Mst1-TG mice, a significant downregulation of numerous nuclear DNA (nDNA)-encoded mitochondrial gene-sets 13 . Using cardiomyocyte-restricted TEAD1-deletion (TEAD1-cKO) models, two independent groups have recently reported rapid onset of DCM phenotype, together with downregulation of mitochondrial genes and mitochondrial dysfunction 16 - 18 , implying a role of TEAD1 in mitochondrial integrity and function 16 - 18 . Being an effector in YAP/TAZ-mediated transcriptional regulation, TEAD1 also interacts with other pathways or transcriptional cofactors 19 .…”