Molecular and Cellular Mechanisms of Copper-Dependent Nutrient Signaling and Metabolism

铜依赖的营养信号传导和代谢的分子和细胞机制 项目总结/摘要 类似于有机营养素，如氧、脂质、氨基酸和碳水化合物，过渡金属铜 (Cu)是正常生理和发育所必需的膳食营养素。几十年的研究强调， 破坏体内平衡机制的生理和疾病相关后果， 铜的获取，储存和分配到铜依赖酶。然而，与 铜有效性的改变不能完全用传统上利用的酶的数量有限来解释。 Cu作为催化辅因子的氧化还原电位。最近在Cu生物学中的发现揭示了Cu的直接结合 在通过蛋白激酶MEK 1/2调节细胞增殖的信号分子内的非催化位点， 通过磷酸二酯酶PDE 3B的脂质代谢和通过自噬激酶ULK 1/2的营养再循环。 这种新模式在营养传感和蛋白质调节中的出现已经确立了Cu是一种 细胞内信号传导的关键介质，提供了存在分子机制的证据 感应铜丰度的变化，并扩大了铜对细胞过程的贡献， 适应营养缺乏。这项拨款提案将集中在铜稳态， 营养信号传导和代谢，通过检查铜传感必要的机制之间的相互作用， 细胞能量稳态和评估的必要性铜代谢的灵活性下营养和 氧应激具体来说，我们将在过去5年的新发现的基础上阐明机制， 的：i）Cu控制的自噬-溶酶体生物发生和功能，ii）Cu介导的代谢灵活性，通过直接 糖酵解通量的控制，以及iii）线粒体Cu转运和细胞溶质营养之间的相互连接 检测新陈代谢所需的信号通路。通过启动这三个相互关联的重点领域，我们 将增加我们对铜依赖酶的分子和细胞特征的基础知识 和细胞过程，并使治疗靶向铜依赖性疾病的脆弱性。

Molecular and Cellular Mechanisms of Copper-Dependent Nutrient Signaling and Metabolism PROJECT SUMMARY/ABSTRACT Akin to organic nutrients, such as oxygen, lipids, amino acids, and carbohydrates, the transition metal copper (Cu) is an essential dietary nutrient for normal physiology and development. Decades of research highlight the physiological and disease associated consequences of disrupting homeostatic mechanisms that ensure proper Cu acquisition, storage, and distribution to Cu-dependent enzymes. However, phenotypes associated with alterations in Cu availability cannot be fully explained by the limited number of enzymes that traditionally harness the redox potential of Cu as a catalytic cofactor. Recent discoveries in Cu biology have revealed direct Cu binding at non-catalytic sites within signaling molecules that modulate cell proliferation via the protein kinases MEK1/2, lipid metabolism via the phosphodiesterase PDE3B, and nutrient recycling via the autophagic kinases ULK1/2. The emergence of this new paradigm in nutrient sensing and protein regulation has established that Cu is a critical mediator of intracellular signaling, provided evidence for the existence of molecular mechanisms for sensing changes in Cu abundance, and expanded the contribution of Cu to cellular processes necessary for adaptation to nutrient scarcity. This grant proposal will focus on the intersections between Cu homeostasis, nutrient signaling, and metabolism by examining the interplay between mechanisms of Cu-sensing necessary for cellular energy homeostasis and evaluating the necessity of Cu for metabolic flexibility under nutrient and oxygen stress. Specifically, we will build on our novel findings from the past 5 years by elucidating mechanisms of: i) Cu-controlled autophagy-lysosomal biogenesis and function, ii) Cu-mediated metabolic flexibility via direct control of glycolytic flux, and iii) interconnectivity between mitochondrial Cu transport and cytosolic nutrient sensing signaling pathways necessary for metabolism. By launching these three interconnected focus areas, we will increase our fundamental knowledge of the molecular and cellular features of Cu-dependent enzymes and cellular processes and enable therapeutic targeting of Cu-dependent disease vulnerabilities.