Regulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and mitochondrial function by MEF2 and HDAC5
Regulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and mitochondrial function by MEF2 and HDAC5
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DOI：
10.1073/pnas.0337639100
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发表时间：
2003-02-18
影响因子：
11.1
通讯作者：
Olson, EN
中科院分区：
文献类型：
--
作者：
Czubryt, MP;McAnally, J;Olson, EN
肌细胞增强因子-2(MEF2)转录因子调控肌肉发育和钙依赖基因表达。组蛋白脱乙酰基酶(HDACs)可抑制MEF2的活性，组蛋白脱乙酰基酶(HDACs)在钙信号作用下，在两个丝氨酸残基上发生磷酸化时，可与MEF2解离。为了探索MEF2//HDAC相互作用在心脏中的潜在重要性，我们产生了在心脏特异性和多西环素诱导的调控下表达信号抗性形式的HDAC5的转基因小鼠。转基因表达导致雄性小鼠猝死，并伴有心肌线粒体丢失和形态改变，线粒体酶表达下调。转录共激活因子PGC-1α是线粒体生物发生和脂肪酸氧化的主要调节因子，也因HDAC5的表达而下调。对PGC-1α启动子的检测发现了两个MEF2结合位点，它们介导IVIEF2的转录激活和HDAC5的抑制。这些发现确定PGC-1α是MEF2/HDAC调节通路的关键靶点，并证明该通路在维持心肌线粒体功能方面的重要性。
The myocyte enhancer factor-2 (MEF2) transcription factor regulates muscle development and calcium-dependent gene expression. MEF2 activity is repressed by class If histone deacetylases (HDACs), which dissociate from MEF2 when phosphorylated on two serine residues in response to calcium signaling. To explore the potential importance of MEF2//HDAC interactions in the heart, we generated transgenic mice expressing a signal-resistant form of HDAC5 under cardiac-specific and doxycycline-inducible regulation. Transgene expression resulted in sudden death in male mice accompanied by loss and morphologic changes of cardiac mitochondria and down-regulation of mitochondrial enzymes. The transcriptional coactivator PGC-1alpha, a master regulator of mitochondrial biogenesis and fatty acid oxidation, was also down-regulated in response to HDAC5 expression. Examination of the PGC-1alpha promoter revealed two MEF2-binding sites that mediate transcriptional activation by IVIEF2 and repression by HDAC5. These findings identify PGC-1alpha as a key target of the MEF2/HDAC regulatory pathway and demonstrate this pathway's importance in maintenance of cardiac mitochondrial function.