Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells

NAD+ serves an essential role as an electron acceptor (via hydride transfer) in central carbon metabolism. In the absence of intracellular NAD+, cells cannot produce ATP. However, even moderate diminishments in NAD+ levels can limit the signaling activity of NAD+-consuming enzymes. NAD+ concentrations differ in different parts of the cell, and there are distinct subcellular requirements for NAD+. Dynamic modulation of subcellular, and possibly extracellular, NAD+ concentrations represent an emerging mechanism for regulating specific NAD+-dependent pathways. Compartmentalization of NAD+ helps to time responses, communicate cellular status, and protect crucial NAD+ pools. Genetically encoded sensors represent promising approaches for additional development to generate a molecular toolbox for measuring and studying fluctuations in levels of compartmentalized NAD+. The numerous biological roles of NAD+ are organized and coordinated via its compartmentalization within cells. The spatial and temporal partitioning of this intermediary metabolite is intrinsic to understanding the impact of NAD+ on cellular signaling and metabolism. We review evidence supporting the compartmentalization of steady-state NAD+ levels in cells, as well as how the modulation of NAD+ synthesis dynamically regulates signaling by controlling subcellular NAD+ concentrations. We further discuss potential benefits to the cell of compartmentalizing NAD+, and methods for measuring subcellular NAD+ levels. The numerous biological roles of NAD+ are organized and coordinated via its compartmentalization within cells. The spatial and temporal partitioning of this intermediary metabolite is intrinsic to understanding the impact of NAD+ on cellular signaling and metabolism. We review evidence supporting the compartmentalization of steady-state NAD+ levels in cells, as well as how the modulation of NAD+ synthesis dynamically regulates signaling by controlling subcellular NAD+ concentrations. We further discuss potential benefits to the cell of compartmentalizing NAD+, and methods for measuring subcellular NAD+ levels. the developmental process by which precursor cells develop into adipocytes (fat cells). separated into isolated or distinct subcellular locales. an enzyme that is located on, and has catalytic activity at, the surface of a cell, directed towards the exterior of the cell. the fraction of a metabolite that is not currently bound to or associated with protein. Typically, this can be considered as the amount of available metabolite. combining more than one assay in a simultaneous analysis. the ordered and regulated series of chemical reactions that lead to the generation of an NAD+ molecule. the use of NAD+ either as a coenzyme in metabolic reactions or as a substrate for degradation. toxic effects on the cell resulting from exposure to illumination from lasers and high-intensity arc-discharge lamps. a biosynthetic pathway that recycles intermediates from a degradative process. refers to a defined location, organelle, or structure within a cell. It can also refer to an event or molecule that occurs or resides within the confines of a particular space within a cell.