线粒体加工的端粒酶RNA产物TERC-53参与器官与个体衰老

Mitochondrial functions and telomere functions have mostly been studied independently. In recent years, it, however, has become clear that there are intimate links among mitochondria, telomeres and telomerase subunits. Mitochondrial dysfunctions cause telomere attrition, while telomere damages lead to reprograming of mitochondrial biosynthesis and mitochondrial dysfunctions, which has important implications in ageing and diseases. In addition, evidence has accumulated that telomere-independent functions of telomerase also exist and that the protein component of telomerase TERT shuttles between the nucleus and mitochondria under oxidative stress. Our previously published data show that the RNA component of telomerase TERC is also imported into mitochondria, processed into TERC-53 and then exported back to the cytosol. Cytosolic TERC-53 is involved in cellular senescence and organismal ageing. This proposal aims to further characterize the regulation of organismal ageing by cytosolic TERC-53 and investigate the mechanism behind the function of TERC-53. It will improve our understanding of normal ageing of mammals and has the potential of providing a new strategy for treating ageing-related diseases.

线粒体功能和端粒功能大多是独立研究的。然而，近年来的研究表明线粒体、端粒和端粒酶之间有着密切的联系。线粒体功能紊乱导致端粒损伤，而端粒损伤导致线粒体生物合成的改变和线粒体功能紊乱，这在衰老和疾病中具有重要意义。此外，有证据表明端粒酶的蛋白组分TERT存在独立于端粒酶的功能，并且在氧化应激条件下从细胞核导出并被导入线粒体。我们先前发表的数据表明，端粒酶的RNA组分TERC也被导入线粒体，加工成TERC-53后再被运输回胞质。胞质的TERC-53参与细胞衰老与器官衰老。本项目旨在进一步研究胞质TERC-53和个体与神经系统衰老之间的关系，并进一步阐明其作用机理。本研究有望推进我们对哺乳动物正常衰老的理解，并提供了一个应对衰老相关疾病的可能策略。

衰老是一个复杂的过程，有多种因素参与。各种相关学说并不是独立存在，而是相辅相成，你中有我，我中有你。我们的前期研究表明线粒体、端粒酶和非编码RNA在衰老过程中协同作用。本项目聚焦于端粒酶的RNA组分TERC的线粒体加工产物TERC-53在衰老中的作用及机理研究。本研究发现Terc-53有效调节小鼠神经瘤母细胞衰老，该作用独立于全长的Terc。机制方面Terc-53作为分子支架介导结合蛋白泛素化降解调控脑细胞衰老。转基因小鼠的研究发现Terc-53加速小鼠正常衰老和认知功能缺陷。该作用是一个随衰老逐渐显露和渐进的过程。另外我们还有证据表明人源TERC-53可能参与了阿尔兹海默症的发生发展。