线粒体DNA拷贝数上调在耳蜗毛细胞凋亡保护中的作用及机制

Sensorineural hearing loss affects a large population and its treatment is still difficult. The apoptosis protection of cochlear hair cells is an important research direction. Some studies have found that the level of mitochondrial DNA copy number can influence cell apoptosis. In our previous study, we found that the increase of mitochondrial DNA copy number in mouse cochlear hair cells might be blocked when the cells were induced apoptosis, while the increase was found in tumor cells and proved to have anti-apoptosis effect. So, in hair cells, the up-regulation of mitochondrial DNA copy number could have apoptosis protection. The up-regulation could enhance the work efficiency of mitochondrial respiratory chain and mitochondrial function, reduce the generation of reactive oxygen species, increase ATP output and stabilize the mitochondrial membrane potential; or inhibite mitochondrial membrane pore opening, reduce the release of pro-apoptosis proteins and maintain a stable mitochondrial membrane potential. In this research, we will take the mouse cochlear hair cells as the research object, clarify the change of mitochondrial DNA copy number in apoptotic hair cells, and increase the mitochondrial DNA copy number through up-regulate the expression of TFAM to analyse its effect on apoptosis protection of hair cells and related mechanisms, in the hope of providing a new idea for the basic research of hearing loss.

感音神经性耳聋影响人口广泛而其治疗仍然是个难题。耳蜗毛细胞的凋亡保护是治疗耳聋的一个重要研究方向。有研究表明，细胞内线粒体DNA拷贝数水平可影响细胞凋亡。在我们前期的研究中发现，小鼠耳蜗毛细胞被诱导凋亡时其线粒体DNA拷贝数的升高可能被抑制，而这种升高在肿瘤细胞中存在且已被证实有抗凋亡作用。因此，在耳蜗毛细胞中，线粒体DNA拷贝数上调很可能有凋亡保护作用。上调的线粒体DNA拷贝数，一方面可增强线粒体内呼吸链工作效率及线粒体功能，减少活性氧产生，增加ATP产出并稳定线粒体膜电位；另一方面可抑制线粒体膜孔道的开放，减少凋亡信号分子的释放并维持线粒体膜电位稳定。在本课题研究中，我们将以小鼠耳蜗毛细胞为研究对象，进一步明确毛细胞凋亡过程中其线粒体DNA拷贝数的变化，同时通过过表达TFAM上调耳蜗毛细胞线粒体DNA拷贝数并分析其在细胞凋亡保护中的作用及可能机制，最终为耳聋的基础研究提供一个新的思路。