TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes
TEAD1 protects against necroptosis in postmitotic cardiomyocytes through regulation of nuclear DNA-encoded mitochondrial genes
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DOI：
10.1038/s41418-020-00732-5
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发表时间：
2021-01-19
影响因子：
12.4
通讯作者：
Zhou, Jiliang
中科院分区：
文献类型：
--
作者：
Liu, Jinhua;Wen, Tong;Zhou, Jiliang
Hippo信号效应子TEAD 1在心血管发育中起着重要作用。然而，TEAD 1在有丝分裂后心肌细胞（CM）中的作用仍不完全清楚。在此，我们报道了TEAD 1是有丝分裂后CM存活所必需的。我们发现，成年小鼠普遍存在或CM特异性Tead 1的损失，目前与急性发作的扩张型心肌病的快速致死。令人惊讶的是，Tead 1的缺失激活了坏死性凋亡途径，诱导了大量的心肌细胞坏死性凋亡，但没有凋亡。与细胞凋亡相反，坏死性凋亡是细胞死亡的促炎形式，并且与此一致，在Tead 1敲除小鼠的心脏中观察到显著更高水平的活化巨噬细胞和促炎细胞因子的标志物。通过给予necrostatin-1阻断坏死性凋亡挽救了Tead 1缺失诱导的心力衰竭。从机制上讲，全基因组转录组和ChIP-seq分析显示，在成年心脏中，Tead 1直接激活了大量核DNA编码的线粒体基因，这些基因是组装电子传递复合物和产生ATP所必需的。Tead 1在成年CM中表达的缺失增加了线粒体活性氧，破坏了线粒体的结构，降低了复合物I-IV驱动的氧消耗和ATP水平，导致坏死性凋亡的激活。这项研究确定了一个意想不到的范例，其中TEAD 1是必不可少的有丝分裂后CM生存维持细胞核DNA编码的线粒体基因的表达所需的ATP合成。
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 pro-inflammatory 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.