Our lab investigates the metabolic mechanisms that regulate cellular and organismal adaptation to physiologic and pathologic stress conditions. Within this context, we study fundamental aspects of metabolic biology, including causes and consequences of cellular fuel utilization patterns and how processing of nutrients/carbon substrates translates into specific metabolic signals that shape cell fate and function. To this end, we apply multi-disciplinary approaches that draw on biochemistry, mouse models, mitochondrial physiology, chemical biology, proteomics and metabolomics. This research program has led to advances in understanding anabolic and catabolic mechanisms that link altered cellular fuel usage and nutrient signaling to diseases such as cancer, diabetes and seizure disorders.
We are broadly interested in basic aspects of metabolic regulation such as cell autonomous and non-autonomous mechanisms that determine cellular fuel choices and fuel flexibility, including substrate supply. These can in turn be influenced by metabolic compartmentalization, spatial organization of metabolic enzymes in macromolecular complexes and their allosteric regulation, functional crosstalks with cellular organelles such as mitochondria and lipid droplets, as well as the cellular microenvironment. The following lines of investigation are examples of our current research efforts related to these topics:
- Metabolic crosstalks and regulation of cellular inflammation. We have recently identified a link between glucose metabolism, mitochondrial pyruvate handling and arginine metabolism through the urea cycle as a cell-intrinsic anti-inflammatory mechanism. Our current research in this area is focused on understanding the physiological functions of this metabolic axis in inflammatory immune cells and their target tissues, and its relevance for immunomodulation in the context autoimmune and other chronic inflammatory diseases.
- Contribution of mitochondrial pathways to metabolic heterogeneity in cancer. Increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis (the Warburg effect), including varied contribution of mitochondria to tumor metabolism. We are investigating cell-autonomous and non-cell autonomous mechanisms underlying fuel preferences in non-Warburg type cancers with a major focus on the role of mitochondria and fatty acid metabolism in tumor growth and survival.
- Neuronal fuel substrate switching and the excitable brain. Glucose is the predominant fuel in the brain, however, neural cells can utilize alternate fuels such as ketone bodies (KBs) with important implication in neuronal excitability and seizure responses. This is also evident from the protective effects of low glycemic or ketogenic diets in pharmacoresistant epilepsy. However, given the systemic effects of diets, it has been difficult to home in on cell autonomous mechanisms that control the choice and direct consequences of glucose vs KB utilization in the brain. We are investigating diet independent, cell autonomous mechanisms that recapitulate this glucose-to-KB fuel switch in neurons to produce anti-seizure effects.
Department of Cancer Biology
Longwood Center, LC-6313
360 Longwood Avenue
Boston, MA 02115