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首页> 外文期刊>Molecular and Cellular Biology >Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle
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Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle

机译：缺乏转录因子Yin Yang 1在骨骼肌中的小鼠的线粒体形态和生物能功能的缺陷。

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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 1α (PGC1α), 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.
机译：功能性线粒体的形成，分布和维持是通过动态过程实现的，该过程严格依赖于编码线粒体蛋白的核基因的转录。这些线粒体基因中的许多在其近端启动子中均含有转录因子Yin Yang 1（YY1）的结合位点，但其生理相关性尚不清楚。我们在这里报告，骨骼肌特异性YY1基因敲除（YY1mKO）小鼠具有严重缺陷的线粒体形态和氧化功能与运动耐受性，线粒体肌病和身材矮小相关。基因集富集分析（GSEA）显示，在YY1mKO小鼠中下调的主要途径与关键的代谢和调控线粒体基因相关。该分析与这些小鼠中线粒体蛋白水平的显着降低和氧化磷酸化（OXPHOS）生物能功能一致。与发现野生型小鼠相反，哺乳动物雷帕霉素靶标（mTOR）的失活不会抑制YY1mKO小鼠的线粒体基因。从机理上讲，YY1的mTOR依赖性磷酸化导致YY1与转录共激活因子过氧化物酶体增殖物激活的受体γ共激活因子1α（PGC1α）之间的强相互作用，PGC1α是线粒体功能的主要调节剂。这些结果强调了YY1在维持线粒体功能中的重要作用，并解释了其失活可能如何导致运动不耐症和线粒体肌病。

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