STTT | NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential


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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. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. 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+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. 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.

Fig. 1 Overview of the NAD+ metabolism and its physiological function  

NAD+ was first described in 1906 as a component that could increase the ferme ntation rate in yeast. Years later, NAD+ was determined to play a vital role for hydrogen transfer in redox reaction. As an essential redox carrier, NAD+ receives hydride from metabolic processes including glycolysis, the TCA cycle, and fatty acid oxidation (FAO) to form NADH. NADH, therefore, serves as a central hydride donor to ATP synthesis through mitochondrial OXPHOS, along with the generation of ROS. 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. Recently, it has been found that NAD+ serves as a nucleotide analog in DNA ligation and RNA capping.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.Through these activities, NAD+ impact energy metabolism, DNA repair, epigenetic modification, inflammation, circadian rhythm and stress resistance. NAD+ deficiency, however, contributes to a spectrum of diseases including metabolic diseases, cancer, aging and neurodegeneration disorders.

Here, authors 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. Furthermore, they 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. 

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