发育时期线粒体应激诱导长寿的表观调控机理研究

线粒体功能障碍被认为是诱导衰老和衰老相关疾病的重要因素之一。但是，在发育早期轻微的损伤线粒体的功能，反而可以诱导线粒体应激反应产生对机体有益的影响，并且延长寿命。我们前期的工作发现：早期的线粒体损伤可以通过特异的表观因子调控染色质结构，诱导线粒体未折叠蛋白质反应（UPRmt），并延长寿命。这一特异的表观调控可以通过改变染色质的结构，将线粒体应激反应的基因调控网络维持到成年以后，最终延缓衰老的进程。因此，我们将利用线粒体损伤诱导的UPRmt作为我们遗传筛选的报告基因，寻找参与调控染色质结构重塑以及衰老的信号因子。对于这些信号因子的进一步研究，可以帮助我们理解当线粒体功能损伤后，是如何激活表观遗传因子参与调控染色质结构，并诱导线粒体应激反应通路，以及延长寿命的分子机制。

Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases. Conversely, however, minor disturbing of mitochondrial function in early life is capable of conferring extraordinary beneficial effects that end with an extended lifespan. The underlying mechanism of how the mitochondrial stress occurred during development influence long-term gene regulation, especially in the lifespan regulation, has only been investigated in recent years. My previous work uncovered that the mitochondrial stress in early life induces extensive chromatin remodeling required for the mitochondrial unfolded protein response (UPRmt). This epigenetic regulation allows for an early, stable remodeling of transcriptional networks and eventually impacts the rate of aging. The obvious induction of UPRmt upon mitochondrial stress is a readily discernable phenotype against which we could set up a screen to identify genes that mediate chromatin structure and longevity. The candidates from this screen will allow us to understand the question of what is the stress signaling released from the mitochondria to initiate the epigenetic changes in order to induce UPRmt and extend lifespan.