Christian M. Metallo
Metabolism plays a role in virtually all cellular processes, and dysfunction in biochemical pathways contributes to the pathogenesis of many diseases, including obesity, metabolic syndrome, cancer, and heart disease. Understanding how nutrients, metabolites, and cofactors flow through intracellular pathways (i.e., metabolic flux) is therefore invaluable for elucidating disease mechanisms and designing new therapies. To quantitatively visualize metabolic pathway activity we apply isotope labeled metabolic tracers to living systems and detect isotope enrichment throughout the metabolome using chromatography coupled to mass spectrometry. The amount of isotope labeled atoms that are incorporated into biomass or other pathways provides information about which enzymes and pathways are most active. Finally, to account for the interconnected nature of metabolic networks we perform systems-level analyses of these data to determine fluxes, since one reaction can influence many other pathways. We apply this approach to various biological systems to quantitatively describe how metabolic function (or dysfunction) contributes to human disease.
Metabolic syndrome and obesity
Metabolic syndromes are emerging as epidemics in the Western world. These diseases involve dysregulation of metabolic homeostasis, particularly in metabolically active tissues such as the liver, muscle, or adipose tissue. Hepatocytes, myocytes, and adipocytes must constantly assess the extracellular microenvironment and respond to changes in nutrient availability by reprogramming metabolic pathways. When these responses go awry disease ensues. For example, oxygen is critical to maintain normal cell function, and limitations in tissue oxygen (hypoxia) occur in numerous pathologies. Changes in oxygen availability have profound effects on lipid and fat metabolism. By applying metabolic flux analysis (MFA) to cells and animals we hope to discover how changes in carbohydrate, protein, amino acid, and lipid metabolism contribute to obesity and metabolic syndrome.
Oncogenes and tumor suppressor proteins induce profound changes in cell behavior to drive tumor progression. Defects in the function of metabolic enzymes or regulatory molecules can promote cancer in this manner. By correlating cancer cell genetics (mutations, deletions, etc.) with metabolic reprogramming we can better understand how metabolic pathways function in patient tumors. Ultimately we hope to use this information to design therapies that target the metabolic enzymes and pathways on which tumors rely most.
Stem cells in the body maintain tissue homeostasis through regeneration and differentiation. Pluripotent stem cells can differentiate to virtually all cell types in the body while serving as model systems for development, drug testing, or genetic diseases. Metabolic processes are important for stem cell maintenance, growth, and differentiation and must be controlled appropriately. Upon differentiation to specific lineages such as cardiomyocytes, cells must perform specific functions that often involve significant metabolic reprogramming. We are applying MFA to understand how metabolism operates in stem cells and changes during lineage specification. These findings may provide better means of controlling pluripotent cell growth and differentiation while enhancing the performance of stem cell derivatives.