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

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.