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

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 45; no. 10; pp. 858 - 873
• Main Authors: Cambronne, Xiaolu A., Kraus, W. Lee
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2020
• Subjects: CD38; nicotinamide mononucleotide adenylyltransferase (NMNAT); nicotinamide phosphoribosyltransferase (NAMPT); poly(ADP-ribose) polymerase (PARP); sirtuin; nicotinamide mononucleotide adenylyltransferase (NMNAT); poly(ADP-ribose) polymerase (PARP); CD38; nicotinamide phosphoribosyltransferase (NAMPT); sirtuin
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2020.05.010

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. 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+.