Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle
Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle
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DOI：
10.1128/mcb.00337-12
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发表时间：
2012-08-01
影响因子：
5.3
通讯作者：
Puigserver, Pere
中科院分区：
文献类型：
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作者：
Blaettler, Sharon M.;Verdeguer, Francisco;Puigserver, Pere
功能性线粒体的形成、分布和维持是通过严格依赖于编码线粒体蛋白的核基因转录的动态过程来实现的。这些线粒体基因中的大量在其近端启动子中含有转录因子 Yin Yang 1 (YY1) 的结合位点，但其生理相关性尚不清楚。我们在此报告，骨骼肌特异性 YY1 敲除 (YY1mKO) 小鼠的线粒体形态和氧化功能存在严重缺陷，与运动不耐受、线粒体肌病迹象和身材矮小相关。基因集富集分析 (GSEA) 显示，YY1mKO 小鼠中下调的主要途径被分配给关键的代谢和调节线粒体基因。该分析与这些小鼠中线粒体蛋白水平和氧化磷酸化（OXPHOS）生物能功能的显着降低一致。与野生型小鼠的发现相反，哺乳动物雷帕霉素靶点（mTOR）的失活并没有抑制 YY1mKO 小鼠的线粒体基因。从机制上讲，YY1 的 mTOR 依赖性磷酸化导致 YY1 与转录共激活剂过氧化物酶体增殖物激活受体 γ 共激活剂 1a (PGC1 α)（线粒体功能的主要调节因子）之间的强烈相互作用。这些结果强调了 YY1 在维持线粒体功能中的重要作用，并解释了它的失活如何导致运动不耐受和线粒体肌病。
The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature. Gene set enrichment analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in the level of mitochondrial proteins and oxidative phosphorylation (OXPHOS) bioenergetic function in these mice. In contrast to the finding for wild-type mice, inactivation of the mammalian target of rapamycin (mTOR) did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator la (PGC1 alpha), a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and explain how its inactivation might contribute to exercise intolerance and mitochondrial myopathies.