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

Abstract

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. Subcellular Compartmentalization of NAD + Synthesis, Catabolism, and FunctionOxidized nicotinamide adenine dinucleotide (NAD + ) is a metabolic cofactor that plays essential roles in all domains of life. In over a century of research on NAD + , great strides have been made in understanding the synthesis, degradation, and biological functions of NAD + (Box 1, Tables 1 and 2). Recent interest in the biology of NAD + has been driven by a desire to modulate its metabolic and signaling pathways to counteract illnesses stemming from metabolic disorders, tumorigenesis, inflammation, cardiovascular disease, neurodegeneration, and the onset of pathologies associated with advancing age. NAD + -utilizing (see Glossary) enzymes localize to specific subcellular compartments where they execute specific subcellular functions, leading to compartmentalization of NAD + synthesis and functions. The classic example of NAD + compartmentalization is the molecular distinction from its reduced counterpart, NADH, as well as from NADP + and NADPH. These differences are readily discerned in lysates and in vitro. Additional forms of compartmentalization, nevertheless, are not readily distinguishable in these preparations.

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

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Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

“…With the exception of the liver where NAD + levels were shown to predominantly depend on tryptophan, many tissues and most transformed cell culture cell lines synthesize NAD + from NAM and thus rely mostly on the salvage pathway [ 38 ]. The salvage pathway depends on the expression level of nicotinamide phosphoribosyltransferase (NAMPT) and the nicotinamide mononucleotide adenylyl transferases (NMNATs), NMNAT1, 2 and 3 [ 42 , 43 ]. The localization of the three NMNATs is described to be enzyme-specific, with NNMAT1 localizing mainly to the nucleus, NMNAT2—to the cytoplasm as well as to the Golgi apparatus and NMNAT3—to the mitochondria [ 44 , 45 , 46 ].…”

Chronic depletion of subcellular NAD pools reveals their interconnectivity and a buffering function of mitochondria

“…Compartment-specific NAD homeostasis has been highlighted in recent studies as an important determinant of physiological processes such as adipocyte differentiation, neuronal cell survival, metabolic regulation of transcription, and electron transport chain activity [39][40][41][42][43][44] .…”