线粒体蛋白TFAM在逆行信号传导以及代谢重编程过程中发挥的作用

线粒体是细胞的能量工厂，含有自身DNA。人类线粒体DNA编码13个呼吸链的组成亚基。其余约99%的线粒体蛋白，包括呼吸链的其他亚基都是由核DNA编码，合成后转位至线粒体。因此线粒体和细胞核之间需广泛交流，以保证呼吸链的正确组装和突发事件的及时应对。从细胞核传向线粒体的信号为顺行信号,反之为逆行信号。哺乳动物细胞中逆行信号的传导分子有多种类型，但已报道的蛋白质类分子仅有两个，即ATF5和GPS2，分别响应线粒体蛋白稳态失衡和线粒体膜电位下降。本课题中我们锁定另一个在线粒体和细胞核均有定位的蛋白TFAM。与ATF5和GPS2不同的是，TFAM能够响应线粒体丙酮酸摄入的变化而发生定位改变，加之其能够结合DNA和调控基因表达，TFAM很有可能在丙酮酸代谢变化所引起的代谢重编程过程中起作用。因而针对该分子的进一步研究将有助于我们了解线粒体代谢变化引起逆行信号的传导机制以及代谢类疾病的发病机理。

Mitochondria are referred to the powerhouse of the cell and contain their own DNA. Human mitochondrial DNA encodes 13 peptides, all of which are subunits of respiratory chain. About 99% of mitochondrial proteins, including other subunits of the respiratory chain, are encoded by nuclear DNA and transferred to mitochondria after synthesis. Thus, mitochondria and nuclei need to communicate extensively to ensure proper assembly of respiratory chains and timely response to emergencies. The signal transduction from the nucleus to the mitochondria is called Anterograde signaling, and vice versa is retrograde signaling. There are many types of molecules that function in retrograde signaling in mammalian cells, but only two protein molecules, namely ATF5 and GPS2, have been reported. They can translocate from mitochondria into the nucleus to regulate the expression of related genes, in response to impaired mitochondrial protein homeostasis and reduced mitochondrial membrane potential, respectively. In this study, we focus on TFAM, another protein that is located in both mitochondria and nucleus. Unlike ATF5 and GPS2, TFAM translocated in response to changes in mitochondrial pyruvate intake. Given its ability to bind DNA and regulate gene expression, TFAM is likely to regulate metabolic reprogramming induced by changes in mitochondrial pyruvate metabolism. Further study on this phenomenon will help us to understand the molecular mechanism of retrograde signaling caused by mitochondrial metabolic changes and the pathogenesis of metabolic diseases.