TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression.
TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression.
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TNFR2 刺激通过 Stat3 和 NF-kB 依赖性 OPA1 表达激活促进线粒体融合
DOI：
10.1161/circresaha.117.311143
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发表时间：
2017-08-04
影响因子：
20.1
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Nan J;Hu H;Sun Y;Zhu L;Wang Y;Zhong Z;Zhao J;Zhang N;Wang Y;Wang Y;Ye J;Zhang L;Hu X;Zhu W;Wang J
补充数字内容可在正文中找到。线粒体是重要的细胞器，在维持细胞结构和功能方面起着至关重要的作用。越来越多的证据表明，肿瘤坏死因子α(Tumor NectorForα，肿瘤坏死因子受体)除了具有促炎和促凋亡作用外，在某些情况下还能促进线粒体完整性和功能的改善，这一现象可归因于肿瘤坏死因子受体2(TnFR2，TnFR2)的存在。本研究旨在探讨肿瘤坏死因子受体2的激活是否以及如何介导肿瘤坏死因子α对线粒体的影响。用针对TNFR1的shRNA处理新鲜分离的新生小鼠心肌细胞，研究TNFR2激活对线粒体功能的影响。新生小鼠心肌细胞表现出线粒体融合的增加，这种变化与线粒体膜电位、细胞内ATP水平和氧耗能力的增加有关。重要的是，TNFR2激活诱导的OPA1(视神经萎缩1)蛋白表达的增加是上述增强的原因，而针对OPA1的siRNA可以减弱这些变化。此外，STAT3和relA都与OPA1的启动子区域结合，它们的相互作用在转录水平上协同上调OPA1的表达。在STAT3与RELA形成超复合体的能力中，STAT3在赖氨酸370或赖氨酸383处的乙酰化起着关键作用。同时，p300调控人胚胎肾293T细胞中STAT3乙酰化，p300介导的STAT3/relA相互作用在OPA1上调中起着不可或缺的作用。最后，在活体横断性主动脉收缩模型中，TNFR2的激活对OPA1的表达产生了有益的影响，在该模型中，TNFR1基因敲除的小鼠比TNFR1和TNFR2基因敲除的小鼠表现出更好的结果。TNFR2的激活通过上调OPA1的表达来保护心肌细胞免受应激。这一过程由p300介导的STAT3乙酰化和STAT3/relA相互作用促进，导致线粒体形态和功能的改善。
Supplemental Digital Content is available in the text. Mitochondria are important cellular organelles and play essential roles in maintaining cell structure and function. Emerging evidence indicates that in addition to having proinflammatory and proapoptotic effects, TNFα (tumor necrosis factor α) can, under certain circumstances, promote improvements in mitochondrial integrity and function, phenomena that can be ascribed to the existence of TNFR2 (TNFα receptor 2). The present study aimed to investigate whether and how TNFR2 activation mediates the effects of TNFα on mitochondria. Freshly isolated neonatal mouse cardiac myocytes treated with shRNA targeting TNFR1 were used to study the effects of TNFR2 activation on mitochondrial function. Neonatal mouse cardiac myocytes exhibited increases in mitochondrial fusion, a change that was associated with increases in mitochondrial membrane potential, intracellular ATP levels, and oxygen consumption capacity. Importantly, TNFR2 activation–induced increases in OPA1 (optic atrophy 1) protein expression were responsible for the above enhancements, and these changes could be attenuated using siRNA targeting OPA1. Moreover, both Stat3 and RelA bound to the promoter region of OPA1 and their interactions synergistically upregulated OPA1 expression at the transcriptional level. Stat3 acetylation at lysine 370 or lysine 383 played a key role in the ability of Stat3 to form a supercomplex with RelA. Meanwhile, p300 modulated Stat3 acetylation in HEK293T (human embryonic kidney 293T) cells, and p300-mediated Stat3/RelA interactions played an indispensable role in OPA1 upregulation. Finally, TNFR2 activation exerted beneficial effects on OPA1 expression in an in vivo transverse aortic constriction model, whereby TNFR1-knockout mice exhibited better outcomes than in mice with both TNFR1 and TNFR2 knocked out. TNFR2 activation protects cardiac myocytes against stress by upregulating OPA1 expression. This process was facilitated by p300-mediated Stat3 acetylation and Stat3/RelA interactions, leading to improvements in mitochondrial morphology and function.