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*
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*
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DOI：
10.1074/jbc.m111.240481
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发表时间：
2011-05
期刊：
影响因子：
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通讯作者：
T. Than;H. Lou;C. Ji;S. Win;N. Kaplowitz
中科院分区：
文献类型：
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作者：
T. Than;H. Lou;C. Ji;S. Win;N. Kaplowitz
过氧化物酶体增殖物激活受体α，辅激活因子1α（PGC-1α）是线粒体生物合成的主要调节因子。PGC-1α的表达受转录因子cAMP反应元件结合蛋白（CREB）的调控。在寻找候选转录因子介导的线粒体应激启动的线粒体到细胞核的信号转导的线粒体生物发生的调节，我们评估了沉默CREB调节的转录共激活因子（CRTC）的影响。CRTC同种型是CREB通过CREB磷酸化非依赖性途径调节转录的共激活剂。使用培养的HepG 2细胞和原代小鼠肝细胞，我们确定了复合物I抑制剂鱼藤酮施加的线粒体应激引起线粒体生物合成，这依赖于PGC-1α的诱导，而PGC-1α的沉默则抑制了线粒体生物合成。通过沉默CRTC 3的表达来抑制鱼藤酮对PGC-1α的诱导，从而阻断下游线粒体的生物合成。相反，沉默CRTC 2不影响响应鱼藤酮的该途径的诱导。因此，CRTC 3在响应鱼藤酮的线粒体生物发生中起选择性作用。
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.