SIRT1通过激活线粒体未折叠蛋白反应改善线粒体功能的机制研究

Mitochondrial dysfunction, including decreased oxidative capacity and increased oxidative damage, is thought to substantially contribute to biological ageing. Sirtuin1 (SIRT1) is a NAD+-dependent protein deacetylase and a longevity regulator which possesses a variety of beneficial anti-ageing activities. However, its role in mitochondria is less known. The mitochondrial unfolded protein response (UPRmt) is a stress response that promotes transcription of nuclear-encoded mitochondrial chaperones to restore protein homeostasis within the organelle. Recent studies revealed that UPRmt activation is associated with lifespan extension in worms and mammalian cells. Although the detail mechanism is unclear, it is likely that mild mitochondrial protein stress results in a broad range of cytosolic and nuclear response which appears to induce a wide-range and cytoprotective effect, which is a key feature of mitohormesis. Our preliminary results demonstrated that SIRT1 overexpression in adipose tissue evoked an up-regulation of mitochondrial stress and UPRmt signaling at young age but prevented the development of metabolic ageing in old mice. Thus, we hypothesize that SIRT1 plays a role in mediating UPRmt. Early-stage activation of SIRT1 can induce a mitohormesis-like effect in mitochondria through UPRmt, which results a long-lasting beneficial effect in mitochondria and whole-body metabolic function. In this study, we will investigate the detail regulatory role of SIRT1 in mitochondria of adipose tissue and skeletal muscle by using our established SIRT1 overexpression or knockout transgenic mouse model. The results from the present study are expected to uncover important insights of mitochondria ageing in metabolic ageing pathways and open new perspectives for drug development.

线粒体功能障碍是衰老的重要特征。SIRT1是一种长寿因子，在调控衰老和寿命方面发挥着重要作用，而其在线粒体的功能尚不清晰。线粒体未折叠蛋白反应（UPRmt）是一种线粒体内积累大量未折叠或错误折叠蛋白的一种应激反应。研究表明，在细胞中适当激活UPRmt能促进细胞产生一系列长效保护性机制，这种效应被称为线粒体低毒兴奋效应（mitohormesis）。我们在SIRT1转基因小鼠中发现脂肪组织过表达SIRT1能在小鼠年轻时期增加线粒体压力，激活UPRmt相关基因表达，并在中老年时期改善小鼠整体代谢功能，延缓衰老。据此我们提出假设：SIRT1介导UPRmt通路。早期激活SIRT1能促进UPRmt信号并通过线粒体低毒兴奋效应改善线粒体功能，延缓衰老。本项目拟采用SIRT1转基因小鼠为模型，阐明SIRT1在骨骼肌和脂肪组织线粒体功能上的关键作用及调控机制，为确立线粒体作为抗衰老新靶点提供科学依据。

线粒体功能障碍是代谢衰老的主要诱因。线粒体未折叠蛋白反应（UPRmt）是一种线粒体内积累大量未折叠或错误折叠蛋白的一种应激反应，是线粒体质量控制机制的一种。研究表明，在细胞中适当激活UPRmt能促进细胞产生一系列长效保护性机制。Sirtuin家族蛋白是一类长寿因子，在在调控衰老和寿命方面发挥着重要作用。我们在研究中发现Sirtuin家族成员SIRT1与SIRT6共同参与线粒体功能调节。在小鼠过表达SIRT1或SIRT6均能改善线粒体与代谢功能，同时敲除SIRT1或SIRT6损害小鼠代谢功能。后续探索中我们发现SIRT6与SIRT1互作，且SIRT6处于SIRT1的下游调控线粒体质量控制相关因子。SIRT6缺失导致线粒体质量控制中未折叠蛋白反应与自噬调节平衡失常，最终导致线粒体功能损伤。在分子机制上，SIRT6去乙酰化线粒体未折叠蛋白反应调控因子mtHSP70并调节其蛋白表达水平。本课题的开展首次揭示Sirtuin家族蛋白在线粒体质量控制调节中的协调效应，对后续临床治疗代谢衰老相关疾病有积极的指导意义。