Abstract 3026 Cracking the CIA code - understanding the molecular basis of Fe-S protein maturation by the cytosolic iron sulfur cluster assembly system

Metabolism is central to virtually all cellular functions and contributes to diseases like cancer, metabolic syndrome, and neuropathy.My laboratory applies stable isotope tracers, mass spectrometry, and metabolic flux analysis (MFA) to quantify metabolism in cells, animal models, and human patients.We are particularly interested in understanding how amino acid and lipid metabolism are coordinated in the context of cancer, diabetes, and neuropathy.A central focus of these studies is sphingolipid biosynthesis via serine palmitoyltransferase (SPT), which integrates amino acid and fatty acid signals into the membrane lipidome through its promiscuity and responsiveness to substrate availability.Here I will detail how we apply MFA and related methods to decipher why serine and glycine are reduced in diabetes and contribute to co-morbidities of diabetes through lipid metabolism.I will also describe efforts in tracing the fates of monounsaturated fatty acids in the context of high-fat diets.We demonstrate that saturated and trans-mono-unsaturated fatty acids are distinctly metabolized by SPT to promote hepatic steatosis and atherosclerosis in low-density lipoprotein receptor (Ldlr)-deficient mice.Finally, I will introduce a framework for applying 13C MFA to elucidate lipid synthesis and recycling pathways in cultured cells and precision-cut tumor slice cultures.We validate this method through characterization of lipid biosynthesis and recycling pathways within lung and pancreatic adenocarcinoma tumors.Collectively, these data provide mechanistic insights into the roles of SPT flux and lipid diversity in driving disease states.