Rheb1通过丙酮酸脱氢酶复合物调节细胞能量产生的机制研究

Misregulation of energy production is correlated with many metabolic and neurodegenerative diseases. The regulation of energy production in mammalian cells is dynamically linked to cellular metabolic demands, by orchestrating glucose oxidation and mitochondrial respiration. mTOR is a master regulator of energy production and associated with a variety of human diseases (diabetes, cancer), but how mTOR controls energy production under physiological condition is not well understood. Our preliminary results demonstrate that genetic deletion of Rheb1, a key activator of mTOR, reduces ATP contents. We extend this finding by examining the molecular mechanism by which Rheb1 regulates cellular energy production. We propose to test the hypothesis that Rheb1 controls the activity of pyruvate dehydrogenase complex through phosphorylation and thus acetyl-CoA biosynthesis. This study will reveal a novel mechanism of Rheb1/mTORC1 control cellular energy production, and facilitate our understanding of the pathology of mTOR-related human diseases.

细胞能量产生异常引起的相关疾病，包括代谢性相关疾病（如糖尿病等）和神经退行性疾病（如阿尔茨海默症等）严重威胁着人类健康。研究表明，哺乳动物细胞内能量产生的调控是精细的动态调节过程，包括对葡萄糖的氧化分解和对线粒体电子传递链活性的调节等。mTOR信号通路在能量产生过程中起重要调节作用，但对其在体内生理状态下调节能量产生的分子机制仍不甚清楚。我们前期研究发现在肝脏敲除mTOR重要活化因子--Rheb1后，能显著降低肝细胞能量产生；并导致其丙酮酸脱氢酶复合物活性显著降低。基于这些发现，我们将利用Rheb1肝脏特异性敲除小鼠，深入开展体内外研究，以验证如下假说：Rheb1通过调节胞内葡萄糖代谢，尤其是控制丙酮酸脱氢酶活性和乙酰辅酶A产生，调控肝细胞能量产生。该研究将有助于揭示Rheb1新的生物学功能和调节细胞内能量产生的分子机制，为相关代谢性疾病的临床治疗提供新的药物靶点和治疗手段。