Regulation of mitochondrial metabolism by SIRT4

项目摘要 衰老是代谢性疾病的主要风险因素，会导致脂肪酸氧化能力下降，但 这种联系的分子机制仍不清楚。蛋白质Sir2(沉默信息调节器) 在模式生物中正向调节衰老，其依赖NAD的酶活性与寿命有关 与新陈代谢有关。哺乳动物有七个Sir2同源基因(sirtuins；SIRT1-7)，它们调节不同方面的 新陈代谢。我们先前发现SIRT4通过抑制氨基酸代谢来调节氨基酸代谢。 谷氨酸脱氢酶(GDH)。我们的新结果表明，SIRT4抑制脂肪酸代谢， 这可能涉及几种机制，包括抑制线粒体中的GDH活性，调节 线粒体生物能量学，以及参与脂肪酸分解代谢的基因转录抑制。我们会 通过多学科方法测试这一假设，包括老鼠生物学、化学和 生物化学。首先，使用SIRT4 KO小鼠的原代肝细胞，我们将检验SIRT4的假设 直接抑制脂肪酸氧化。然后，我们将研究SIRT4对线粒体能量的影响 从氨基酸和脂肪酸中生产。第二，我们将调查调解 SIRT4对脂肪酸氧化的调节作用。第三，我们将利用SIRT4 KO小鼠来测试SIRT4在 哺乳动物的寿命以及在衰老和代谢应激过程中脂肪酸氧化的调节。这些 研究可能对衰老过程中脂肪酸氧化的分子调控提供重要的见解。

Project Summary Aging is a major risk factor for metabolic disease and results in a decline in fatty acid oxidation, but the molecular mechanisms for this association are still unclear. The protein Sir2 (Silent Information Regulator) positively regulates aging in model organisms, and its NAD-dependent enzymatic activity connects lifespan with metabolism. Mammals have seven Sir2 homologs (sirtuins; SIRT1-7), which regulate distinct aspects of metabolism. We previously discovered that SIRT4 regulates amino acid metabolism via the inhibition of glutamate dehydrogenase (GDH). Our new results suggest that SIRT4 suppresses fatty acid metabolism, which likely involves several mechanisms, including inhibition of GDH activity in mitochondria, regulation of mitochondrial bioenergetics, and transcriptional repression of genes involved in fatty acid catabolism. We will test this hypothesis through a multi-disciplinary approach, including mouse biology, chemistry and biochemistry. First, using primary hepatocytes from SIRT4 KO mice, we will test the hypothesis that SIRT4 directly suppresses fatty acid oxidation. Then, we will investigate the effect of SIRT4 on mitochondrial energy production from amino acids and fatty acids. Second, we will investigate mechanisms that mediate the regulation of fatty acid oxidation by SIRT4. Third, we will utilize SIRT4 KO mice to test the role of SIRT4 in mammalian lifespan and in the regulation of fatty acid oxidation during aging and metabolic stress. These studies may provide important insights into the molecular regulation of fatty acid oxidation during aging.