Direct control of mitochondrial dynamics by regulatory amino acids

通过调节氨基酸直接控制线粒体动力学

• 批准号: RGPIN-2018-05162
• 负责人: Chan, Edmond
• 金额: $ 6.12万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746084
• 关键词: Direct; control; mitochondrial; dynamics; regulatory

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.

我们身体的几乎每个细胞都含有数百个线粒体，它们提供一系列基本功能，包括生成ATP。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，后来被一个更大的细胞吞没，形成了一种共生关系，并在进化中幸存下来。反映了这种细菌起源，我们的线粒体通过扩张现有的细胞器然后分裂（又名裂变）进行复制。线粒体也有能力结合在一起（又名融合）形成相互连接的网络。我们现在认识到，融合可以通过减少DNA突变、结合线粒体基因组和预防细胞死亡等多种方式改善线粒体功能。因此，更好地了解线粒体融合和功能可能会带来新的策略，以解决与衰老相关的细胞能量和代谢的缓慢下降。当我们研究细胞如何对营养应激作出反应时，我们发现了氨基酸刺激线粒体强灌注的新途径。这些反应不能用目前理解的机制来解释，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。尽管线粒体依赖于这些营养物质，但线粒体感知氨基酸的运输途径尚不清楚。由于这代表了生物学中一个需要进一步细节的关键问题，我们选择使用我们的系统来探索这个领域。我们将确定氨基酸和低灌注如何帮助支持线粒体内更高水平的代谢。最后，为了控制这一途径，我们需要了解调控机制，以便我们定义驱动营养依赖性线粒体融合的细胞信号模式。为了解决这些问题，我们将培训一组HQP，他们将获得使用细胞生物学高功率技术的经验，包括CRISPR基因靶向，代谢组学和磷蛋白质组学。我们在这里的研究项目将为加拿大线粒体生物学研究界在营养传感方面贡献一个新的领域。