The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways

Abstract

A century after the identification of a coenzymatic activity for NAD(+), NAD(+) metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD(+) have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD(+)-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD(+) provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD(+)-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD(+) production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD(+); and 3) novel data that show how modulation of NAD(+)-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.

In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences

“…These enzymes were found to play important roles in cellular signaling related to cell death, Ca 2+ homeostasis, and lifespan extension, and their activities are highly dependent on the level of NAD + available in the cell (4,5,8,9,33,41,42). In this study, other than the decreases in the intracellular NAD + level and RX (or RP), we also observed a slower decline of the total intracellular NAD content in the human brain during healthy aging, which collectively reflects reduced NAD + availability in the aged brain.…”

“…It has been shown that, by supplying NAD + precursors or intermediates and/or introducing PARPs or CD38 inhibitor, one could enhance the NAD + biosynthesis and/or inhibit its consumption, thus boosting the intracellular NAD + level (6,10,11,43). Such interventions are suggested to promote therapeutic effects of lifespan extension and neuroprotection and could potentially be used with other physiological managements, such as calorie restriction, fasting, or exercise, to compensate for the natural decline of brain NAD + in normal aging and prevent or treat age-related metabolic disorders (3,4,33,44,45).…”

“…NAD is known to convert between its oxidized NAD + and reduced NADH forms during the breakdown of nutrients; hence, the intracellular NAD + /NADH redox state reflects the metabolic balance of the cell in generating ATP energy through oxidative phosphorylation in mitochondria and/or glycolysis in cytosol (2). More recently, after several protein families associated with cell survival were found to use NAD + as their main substrate with activities also regulated by the availability of the NAD + , the full extent of the NAD's function as a metabolic regulator began to unfold (3)(4)(5). A growing number of studies have indicated that NAD + can modulate metabolic signaling pathways and mediate important cellular processes, including calcium homeostasis, gene expression, aging, degeneration, and cell death; therefore, the cellular NAD could serve as a therapeutic target for treating various metabolic or age-related diseases and promoting longevity (6)(7)(8)(9)(10)(11)(12).…”

Intracellular β-Nicotinamide Adenine Dinucleotide Inhibits the Skeletal Muscle ClC-1 Chloride Channel

“…In addition to its role in redox metabolism, proteins such as the sirtuins are regulated by, and consume, NAD ϩ , allowing them to act as metabolic sensors that can regulate downstream metabolic pathways (19). Metabolites of NAD ϩ that result from these enzymatic reactions potently mobilize intracellular Ca 2ϩ stores by acting directly on ryanodine receptors (20) as well as unidentified receptors in other compartments (21) and activate Ca 2ϩ influx carried by TRPM2 channels (22).…”

PLGA‐PNIPAM Microspheres Loaded with the Gastrointestinal Nutrient NaB Ameliorate Cardiac Dysfunction by Activating Sirt3 in Acute Myocardial Infarction

“…In case of the hydrolyzing of NAD + and transferring of the lysine‐bound acetyl group, the loop was moved, and the binding site was blocked, followed by activator release and deacetylated product dissociation. On the other hand, the hydrolyzed product of NAD + was nicotinamide (NAM), and the transferred product of the lysine‐bound acetyl group was 2′‐O‐acetyl adenosine diphosphate(ADP)‐ribose; NAM was transferred to nicotinamide mononucleotide(NMN) by nicotinamide phosphoribosyl transferase (NAMPT), and then the NMN was transferred back to NAD + by nicotinamide mononucleotide adenylyltransferase (NMNAT), forming the NAD + cycle 22, 23. The above results indicated that NaB could contribute to the stabilization of the Sirt3/substrate complex by ordering the “adaptable loop”, leading to the deacetylation of the enzyme for the substrate through stabilized exposure to the “active site”.…”