Metabolic Regulation of Mitochondrial Function

项目总结/摘要 每个细胞都必须不断监测其能量水平，并适当调整能量产生 速率，基于维持体内平衡的代谢需求。持续不断地满足这种能量 需求取决于充足的养分供应，感知养分的可用性，代谢和 转化为化学能。在真核细胞中，能量主要以ATP的形式产生， 通过线粒体。不仅产生了多少总ATP，局部能量水平也很重要 对于细胞执行关键功能，例如神经元活动、细胞迁移、肿瘤细胞侵袭， 伤口愈合和免疫力线粒体形态的细胞内运输和定位 ATP分布的时空异质性。我的总体目标是了解 调节细胞代谢、线粒体定位和 功能估计哺乳动物细胞的线粒体蛋白质数量约为1，300。后 翻译修饰可以进一步放大蛋白质的功能多样性。代谢通量- 敏感翻译后修饰，O-GlcNAc酰化，独特地将营养状态与 细胞代谢和信号通路。虽然我的研究将集中在O- 线粒体功能和细胞器间的GlcN酰化依赖性调节 通信，细胞内空间内代谢酶功能的系统分析 将为我们对代谢途径的理解增加额外的维度。我们的实验将 在细胞生物化学和代谢动力学的背景下破译代谢生物化学和代谢动力学 架构我的跨学科研究计划准备揭示基本的见解， 协调营养和能量供应的机制，并确定潜在的 导致疾病的能量损伤的原因。

Project Summary/Abstract Every cell must constantly monitor its energy level and appropriately adjust energy generation rates, based on metabolic demand to maintain homeostasis. Continuous fulfillment of this energy demand depends on sufficient nutrient supply, sensing nutrient availability, metabolizing and converting into chemical energy. In eukaryotic cells energy, in the form of ATP, is mainly produced by mitochondria. Not only how much total ATP is generated, local energy level is also important for cells to carry out critical functions, such as neuronal activity, cell migration, tumor cell invasion, wound healing, and immunity. Intracellular transport and positioning of mitochondria shape spatiotemporal heterogeneity in ATP distribution. My overall goal is to understand the molecular pathways regulating the interplay between cellular metabolism, mitochondrial positioning and function. The estimated mitochondrial protein number is ~1,300 for mammalian cells. Post- translational modifications can further magnify the functional diversity of proteins. Metabolic flux- sensitive post-translational modification, O-GlcNAcylation, uniquely couple nutrient status to cellular metabolism and signaling pathways. While my research will be focused on O- GlcNAcylation-dependent regulation of mitochondrial functions and inter-organelle communications, systematic analysis of metabolic enzyme functions within the intracellular space will add extra dimension to our understanding of metabolic pathways. Our experiments will decipher the metabolic biochemistry and metabolite kinetics within the context of cellular architecture. My interdisciplinary research program is poised to reveal fundamental insights into the mechanisms that orchestrate the nutrient and energy supply, and pinpoint the underlying causes of energy impairments that lead to diseases.