Direct control of mitochondrial dynamics by regulatory amino acids

*我们体内的几乎每个细胞都包含数百个线粒体，这些线粒体提供包括生成ATP在内的一系列基本功能。生物学中一个真正令人着迷的假设是，线粒体曾经是自由生活的细菌，后来被更大的细胞吞噬，形成了一种共生关系，在进化中幸存下来。反映这种细菌起源的是，我们的线粒体通过扩张现有的细胞器进行复制，然后进行分裂(又名分裂)。线粒体也有能力连接在一起(也就是融合)形成相互连接的网络。我们现在认识到，融合通过减少DNA突变、合并线粒体基因组和防止细胞死亡等多种方式改善线粒体功能。因此，更好地了解线粒体的融合和功能可能会导致新的策略，以应对与衰老有关的细胞能量和新陈代谢的缓慢下降。当我们研究细胞如何对营养压力做出反应时，我们发现了一种新的途径，在这种途径中，氨基酸刺激了强烈的线粒体过度融合。这些反应不能用目前已知的机制来解释，所以在这里，我们将研究这种线粒体重塑，并提供可能影响生物学和医学许多领域的新的基础知识。尽管线粒体依赖于一系列营养物质，但线粒体感知氨基酸的运输途径还不是很清楚。由于这是生物学中的一个关键问题，需要进一步的细节，我们选择使用我们的系统来探索这一领域。我们将确定氨基酸和超融合如何帮助支持线粒体内更高水平的新陈代谢。最后，为了控制这一途径，我们需要了解调控机制，这样我们才能定义驱动营养依赖型线粒体融合的细胞信号模式。为了解决这些问题，我们将培训一批HQP，他们在细胞生物学方面获得了高功率技术的经验，包括CRISPR基因靶向、代谢组学和磷酸蛋白质组学。我们在这里的研究计划将为加拿大的线粒体生物学研究社区贡献一个新的营养传感领域。

***Almost every cell in our body contains hundreds of mitochondria that provide a range of essential functions including the generation of ATP. A truly fascinating hypothesis in biology is that mitochondria were once free-living bacteria, which became engulfed by a larger cell, to form a symbiotic relationship that survived evolution. Reflecting this bacterial origin, our mitochondria replicate by expansion of existing organelles followed by division (aka fission). Mitochondria also have the ability to join together (aka fusion) to form interconnected networks. We are now appreciating that fusion improves mitochondrial function in multiple ways, by decreasing DNA mutations, combining mitochondrial genomes and prevention of cell death. Better understanding of mitochondrial fusion and function could therefore lead to new strategies for tackling the slow decline of cell energetics and metabolism linked to aging. As we studied how cells respond to nutrient stress, we uncovered a novel pathway where amino acids stimulated strong mitochondrial hyperfusion. The responses cannot be explained by currently understood mechanism so here, we will study this mitochondrial remodelling and provide new fundamental knowledge that may impact many areas of biology and medicine. The transport pathways that allow mitochondria to sense amino acids are not well understood, despite the fact that mitochondria rely on a range of these nutrients. Since this represented a key question in biology that needed further detail, we chose to explore this area using our system. We will determine how amino acids and hyperfusion help support higher levels of metabolism within the mitochondria. Lastly, to allow control of this pathway, we need to understand the regulatory mechanisms so we will define the cell signalling patterns that drive nutrient-dependent mitochondrial fusion. To address these questions, we will train a group of HQP who gain experience using high-powered techniques in cell biology including CRISPR gene-targeting, metabolomics and phosphoproteomics. Our research program here will contribute a new area on nutrient sensing to the mitochondrial biology research community in Canada.