NADPH plays an essential role in antioxidant defense and regulates cellular signaling via NADPH oxidases (NOXs). NADH, in turn, drives the generation of ATP via OXPHOS, the production of lactic acid from pyruvate, and the desaturation of PUFAs. NAD + can be reduced into NADH in the metabolic processes, including glycolysis, fatty acid oxidation and the TCA cycle. Mammalian cells can synthesize NAD + de novo from tryptophan by the kynurenine pathway or from NA by the PreissâHandler pathway, while most NAD + is recycled via salvage pathways from nicotinamide (NAM), a by-production of NAD +-consuming reactions. Overview of the NAD + metabolism and its physiological function. Furthermore, we will discuss the NAD + and its metabolites serving as an essential hub in both physiological and pathophysiological processes and explore the potential of NAD + modulation in the clinical treatment of diseases. Here, we summarize recent advances in our understanding of the NAD + homeostasis in response to growth conditions or environmental stimuli, highlighting the actions of NAD + in coordinating metabolic reprogramming and maintaining cellular physiologic biology, which enables the plastic cells to adapt to environmental changes. NAD + deficiency, however, contributes to a spectrum of diseases including metabolic diseases, cancer, aging and neurodegeneration disorders. 9, 10, 11, 12, 13 Through these activities, NAD + impact energy metabolism, DNA repair, epigenetic modification, inflammation, circadian rhythm and stress resistance. 7, 8 Therefore, the dynamic NAD + and its metabolites levels, in response to diverse cellular stress and physiological stimuli, rewire biological processes via post-synthesis modification of fundamental biomolecules, including DNA, RNA and proteins. 3, 4, 5, 6 Recently, it has been found that NAD + serves as a nucleotide analog in DNA ligation and RNA capping.
Beyond its vital role as a coenzyme in energy metabolism, the important role of NAD + has expanded to be a co-substrate for various enzymes including sirtuins, PARPs, CD157, CD73, CD38 and SARM1. NADH, therefore, serves as a central hydride donor to ATP synthesis through mitochondrial OXPHOS, along with the generation of ROS. 2 As an essential redox carrier, NAD + receives hydride from metabolic processes including glycolysis, the TCA cycle, and fatty acid oxidation (FAO) to form NADH. 1 Years later, NAD + was determined to play a vital role for hydrogen transfer in redox reaction. NAD + was first described in 1906 as a component that could increase the fermentation rate in yeast. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD +-regulated physiological responses to stresses, the contribution of NAD + deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention. Prolonged disequilibrium of NAD + metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. Besides, multiple NAD +-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP +. These effects are mainly achieved by the driving effect of NAD + on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Nicotinamide adenine dinucleotide (NAD +) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics.