Svetlana Lutsenko
Research Interests
Copper homeostasis: mechanism of transport, protein and metabolic networks, integrative approaches to human disease
Copper plays an essential role in human physiology. It is an essential cofactor of enzymes that are required for respiration, biosynthesis of neurotransmitter, detoxification of radicals, blood clotting, connective tissue formation, and many others processes. Recent data suggest that coppers serves as a signaling molecules and regulates myelination of neurons, inflammatory response, and angiogenesis. Copper also alters the sensitivity of cancer cells to chemotherapeutic drugs, such as cisplatin. The long-term goal of our research is provide a detailed understanding of human copper homeostasis in health and disease.
Structure, Function, and Regulation of Human Copper Transporters
In human cells, copper levels are controlled by two copper-transporting ATPases, ATP7A and ATP7B. Genetic mutations in ATP7A result in a systemic copper deficiency, particularly in the CNS, and Menkes disease. Menkes disease has a profound effect on human growth and development, and is mostly fatal. Mutations in another copper transporter, ATP7B, are associated with copper accumulation in tissues, particularly in the liver, and Wilson disease. Wilson disease affects primarily children and young adults and has hepatic, neurologic and psychiatric manifestations.
Our group studies the function and regulation of ATP7A and ATP7B in different cell types. We use a combination of biochemical, biophysical, and cell biological approaches to understand the mechanism of copper transport and effects of mutations on the structure and activity of copper transporters. The intracellular localization of ATP7A and ATP7B is regulated by changes in copper levels and hormones. By using site-directed mutagenesis and regulated expression of copper transporters in mammalian cells, we investigate how ATP7A and ATP7B sense changing copper levels and adjust their intracellular location and activity. Through a collaborative whole-genome screening we identified novel regulators of copper homeostasis and we are investigating their role in activity, stability, and trafficking of copper transporters.
Copper chaperones
The intracellular concentration of free copper is tightly controlled. In a cytosol, copper is carried around by small shuttle proteins called copper chaperones or metallochaperones. These proteins distribute copper to different cellular destinations (cytosol, mitochondria, secretory pathway) and modulate activity of their target enzymes. We have discovered that the copper-chaperone Atox1 is a redox sensitive molecule that serves as an important switch directing more copper towards the secretory pathway during neuronal differentiation. We have developed a mouse model for targeted deletion of Atox1 and plan to better understand the role of Atox1 in copper metabolism in the brain
Molecular Mechanisms of Wilson disease
Copper misbalance has severe consequences for cell physiology. We are using the genetically engineered mice with a global and tissue specific deletions of ATP7B to better understand (i) the molecular and cellular events that trigger the onset of pathology in different tissues, (ii) the mechanism of disease progression, and (iii) the role of various metabolic pathways in specific disease manifestations. Our goal is to generate a comprehensive and predictive model for Wilson disease. To achieve this goal, we investigate the copper-induced changes at a single cell level and combine these studies with a large-scale analysis of a proteome, metallome and transcriptomes. We have identified lipid metabolism and liver nuclear receptors as important players in disease pathogenesis and are developing new therapeutic approaches for Wilson disease