Systemic Effects of Copper Deficiency on Host Metabolism and Physiology

PROJECT SUMMARY Essential metals are crucial for metabolic functions, with about 40% of enzymes requiring metal ions for catalysis. Deficiencies in these metals can disrupt various metabolic pathways and affect systemic physiological processes. Although the interactions between individual enzymes and metals are well- documented, predicting the broader metabolic impacts of multiple enzyme alterations due to metal deficiencies remains challenging. This project focuses on copper, an essential but understudied trace metal vital for various enzymes in central metabolism. Copper deficiency is linked to systemic disorders such as myeloneuropathy, anemia, Menkes disease, liver disease, and cardiomyopathy. The project aims to explore the systemic effects of copper deficiency, which is becoming increasingly prevalent due to factors like ultra-processed diets or malabsorption disorders. Using the tractable model organism Caenorhabditis elegans, this study aims to map how copper deficiency alters metabolic networks and to explore its direct and microbiota-mediated physiological effects. This endeavor is critical as it can lead to earlier diagnoses and more effective treatments of associated metabolic disorders by providing a clearer understanding of metabolic changes. Aim 1 delineates the metabolic rewiring in copper-limited C. elegans by evaluating changes in metabolism, physiological parameters such as development and embryonic viability, and sensitivity to metabolic gene knockouts. Initial studies using GC-MS have demonstrated significant alterations in the metabolome of C. elegans when treated with copper chelators, indicating that copper depletion impacts a range of metabolic pathways. Aim 2 focuses on distinguishing the microbiota-dependent and independent effects of copper limitation. The rationale behind this investigation stems from the significant role host-microbiota interactions play in nutrient metabolism. The C. elegans model provides an opportunity to isolate the impacts of bacterial metabolism on host response to copper status, which remains poorly understood in more traditional animal models. Preliminary efforts involve creating a controlled environment where E. coli, the primary food source, is manipulated to vary in metal content. The broader goal of this project is to elucidate the systemic effects of copper as a micronutrient on both the host and its microbiome, which can be expanded to study other essential trace metals. Given the prevalence of copper deficiency and its link to various diseases, this research holds significant potential for advancing our understanding of metabolic network rewiring and its implications for human health.