Original Publication: NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus Cantó, Carles et al. Cell Metabolism , Volume 22 , Issue 1 , 31 - 53 DOI: http://dx.doi.org/10.1016/j.cmet.2015.05.023HighlightsAdaptive cellular metabolism relies on NAD+ to mediate energy signalingNAD+ therapeutics is showing its potential to treat diseaseMetabolic syndrome, cancer, and aging all involve NAD+ signalingNAD+ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD+ metabolism revived interest in NAD+-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD+ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.IntroductionThe importance of nicotinamide adenine dinucleotide (NAD+) metabolism became apparent subsequent to the study of pellagra, a disease characterized by a darkly pigmented skin rash, dermatitis, diarrhea, and dementia, later resulting in death (Sydenstricker, 1958). A century ago, pellagra was common in rural areas of Europe and became an epidemic in the southern United States (Sydenstricker, 1958). However, in 1914, Joseph Goldberger tested whether pellagra was caused by a dietary deficiency and discovered that substituting corn-based diets with milk, eggs, and meat prevented and cured the condition (reprinted essay, Goldberger, 2006). Later, Conrad Elvehjem found that a nicotinamide (NAM)-enriched fraction from deproteinized liver and a sample of crystalline nicotinic acid (NA) cured pellagra (Elvehjem, 1940). NA and NAM, collectively termed niacin or vitamin B3, are now known as precursors for NAD+, an essential element for all cells (Bogan and Brenner, 2008, Chi and Sauve, 2013, Houtkooper et al., 2010a). Whereas pellagra remains endemic in underdeveloped countries (Seal et al., 2007), it is rare in developed countries and mostly occurs in association with tuberculosis, malabsorption, alcoholism, and eating disorders (Hegyi et al., 2004). Less severe niacin deficiencies are more difficult to detect and are linked with low metabolism, cold intolerance, and delayed brain development (Forbes and Duncan, 1961, Williams and Dunbar, 2014).So, what is NAD+, and why is it important? NAD+ was originally described more than 100 years ago by Sir Arthur Harden and colleagues as a cofactor in fermentation (Harden and Young, 1906). Years later, another Nobel prize laureate, Hans von Euler-Chelpin, identified this factor as a nucleoside sugar phosphate (1940 Nobel lecture; Euler-Chelpin, 1929). Yet it took a third Nobel laureate, Otto Warburg, to isolate NAD(P)+ and discover its key role for hydrogen transfer in biochemical reactions (Warburg et al., 1935). NAD+ and NADP+ perform similar redox functions within the cell, but the latter is more confined to biosynthetic pathways and redox protective roles (reviewed in Ying, 2008). Playing a vital role in energy metabolism within eukaryotic cells, NAD+ accepts hydride equivalents to form reduced NADH, which furnishes reducing equivalents to the mitochondrial electron transport chain (ETC) to fuel oxidative phosphorylation. The roles of NAD+, however, have expanded beyond its role as a coenzyme, as NAD+ and its metabolites also act as degradation substrates for a wide range of enzymes, such as sirtuins (Blander and Guarente, 2004, Haigis and Sinclair, 2010, Hall et al., 2013, Houtkooper et al., 2010a). Through these activities, NAD+ links cellular metabolism to changes in signaling and transcriptional events. Here, we give an overview of the current knowledge on NAD+ metabolism, including its biosynthesis, compartmentalization, degradation, and actions as a signaling molecule.NAD+: Metabolic and Therapeutic InterestsFood Sources and Bioavailability of NAD+The daily requirements for NAD+ biosynthesis can be met with the consumption of less than 20 mg of niacin (Bogan and Brenner, 2008). Four major molecules have been described as the root substrates for different NAD+ biosynthetic pathways: the amino acid tryptophan (Trp), NA, NAM, and nicotinamide riboside (NR) (Figures 1A, 1B, and 1D). However, intermediate compounds of these NAD+ biosynthetic pathways, such as nicotinamide mononucleotide (NMN), can also directly stimulate NAD+ synthesis. Vitamin B3 deficiency occurs on low-protein diets or diets relying mostly on untreated maize. Interestingly, niacin is found in maize but is not bioavailable unless given an alkali treatment, a process used in Aztec and Mesoamerican times termed nixtamalization (Gwirtz and Garcia-Casal, 2014). In animal products, and probably in all uncooked foods, the NAD+ and NADP+ cellular content accounts for much of their dietary niacin content (Gross and Henderson, 1983), yet, as exemplified above with corn nixtamalization, their bioavailability might be affected by food processing or cooking.