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Role of cAMP-responsive Element-binding Protein (CREB)-regulated Transcription Coactivator 3 (CRTC3) in the Initiation of Mitochondrial Biogenesis and Stress Response in Liver Cells*

机译:cAMP反应元件结合蛋白(CREB)调控的转录共激活因子3(CRTC3)在肝细胞线粒体生物发生和应激反应中的作用*

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摘要

Peroxisome proliferator-activated receptor α, coactivator 1α (PGC-1α) is the master regulator of mitochondrial biogenesis. PGC-1α expression is under the control of the transcription factor, cAMP-responsive element-binding protein (CREB). In searching for candidate transcription factors that mediate mitochondrial stress-initiated mitochondria-to-nucleus signaling in the regulation of mitochondrial biogenesis, we assessed the effect of silencing CREB-regulated transcription co-activators (CRTC). CRTC isoforms are co-activators of CREB-regulated transcription by a CREB phosphorylation-independent pathway. Using cultured HepG2 cells and primary mouse hepatocytes, we determined that mitochondrial stress imposed by the complex I inhibitor rotenone elicited mitochondrial biogenesis, which was dependent on an induction of PGC-1α, which was inhibited by silencing PGC-1α. PGC-1α induction in response to rotenone was inhibited by silencing the expression of CRTC3, which blocked downstream mitochondria biogenesis. In contrast, silencing CRTC2 did not affect the induction of this pathway in response to rotenone. Thus, CRTC3 plays a selective role in mitochondrial biogenesis in response to rotenone.
机译:过氧化物酶体增殖物激活受体α,共激活因子1α(PGC-1α)是线粒体生物发生的主要调节剂。 PGC-1α的表达受转录因子cAMP反应元件结合蛋白(CREB)的控制。在寻找可调节线粒体生物发生调控中线粒体应激启动的线粒体至细胞核信号转导的候选转录因子时,我们评估了沉默CREB调控的转录共激活因子(CRTC)的作用。 CRTC亚型是CREB磷酸化非依赖性途径共同激活CREB调控的转录。使用培养的HepG2细胞和原代小鼠肝细胞,我们确定了由复合I抑制剂鱼藤酮施加的线​​粒体应激引起了线粒体生物发生,这依赖于PGC-1α的诱导,而PGC-1α的诱导则被沉默。通过沉默CRTC3的表达来抑制鱼藤酮对PGC-1α的诱导,从而阻止下游线粒体的生物发生。相反,沉默CRTC2不会影响鱼藤酮的这一途径的诱导。因此,CRTC3在响应鱼藤酮的线粒体生物发生中起选择性作用。

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