Understanding How Metabolic Cofactors Control Cell Function and Fate

University Of California Los Angeles, Los Angeles CA

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Abstract

PROJECT SUMMARY In the past two decades, the conceptual framework describing how metabolism interfaces with cell biology has fundamentally changed. Once largely considered an adaptive process that conforms to energy demands and cellular cues, it is now clear that metabolism itself can be an important regulator of cell function and fate. This paradigm shift has been driven by studies showing that the concentration and localization of specific metabolites can control physiological processes such as cell signaling, redox homeostasis, epigenetic and post- translational modification, and antimicrobial immunity. Over the next five years, our goal is to apply these principles to a widely-overlooked aspect of metabolism: metabolic cofactors. Cofactors such as coenzyme A (CoA) and nicotinamide adenine dinucleotide (NAD+) are generally thought to exist in excess and merely as passive facilitators of enzymatic reactions, with the exception of NAD+ as a substrate for deacetylases and DNA repair enzymes. However, data generated during our previous project period inform our central hypothesis that the abundance and localization of metabolic cofactors can regulate cell fate and function in entirely novel, previously undescribed ways. We will examine this concept in two subprojects. In the first, we will extend our findings that CoA is a Toll- like receptor 4 (TLR4) agonist and test the hypothesis that CoA can act cell-extrinsically as a damage-associated molecular pattern (DAMP) to prime macrophages for the resolution of inflammation. We will identify the genetic and molecular mechanisms underlying this priming, determine the extent to which other metabolic DAMPs trigger similar pathways and processes as CoA, and test whether interventions that increase physiological CoA levels can promote resolution. In the second subproject, we will follow preliminary data showing that mitochondria from pancreatic b-cells and neurons have an uncommonly high capacity for NAD+ transport across the mitochondrial inner membrane. This informs our hypothesis that mitochondrial NAD+ transport in electrically excitable cells can regulate vesicular exocytosis of insulin (b-cells) and glutamate (neurons). We will identify the mechanisms underlying high mitochondrial NAD+ transport capacity in these cells, define the directionality of transport during cell activation, and determine the effect of modulating NAD+ compartmentation on neuronal and b-cell exocytosis. The proposed projects will further our laboratory’s broader efforts to study how metabolism can regulate cell fate and function. Moreover, they will expand and evolve our understanding of the role of metabolic cofactors in cell biology and disease.