NAD+ homeostasis in human health and disease

Abstract

Depletion of nicotinamide adenine dinucleotide (NAD⁺ ), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in humans. Primary deficiencies of NAD⁺ homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD⁺ homeostasis, such as increased NAD⁺ consumption or dietary deficiency of its vitamin B3 precursors. NAD⁺ depletion can manifest in a wide variety of pathological phenotypes, ranging from rare inherited defects, characterized by congenital malformations, retinal degeneration, and/or encephalopathy, to more common multifactorial, often age-related, diseases. Here, we discuss NAD⁺ biochemistry and metabolism and provide an overview of the etiology and pathological consequences of alterations of the NAD⁺ metabolism in humans. Finally, we discuss the state of the art of the potential therapeutic implications of NAD⁺ repletion for boosting health as well as treating rare and common diseases, and the possibilities to achieve this by means of the different NAD⁺ -enhancing agents.

Keywords: NAD+; NAD+ homeostasis; disease; metabolism; therapy.

Figure 1. NAD⁺ synthesis pathways

NAD⁺ can be synthesized de novo from tryptophan, through the Preiss–Handler pathway from NA or via salvage of the NAD⁺ precursors NMN, NR, NMNH, or NRH. ACMS: aminocarboxymuconate‐semialdehyde; ACMSD: aminocarboxymuconate‐semialdehyde decarboxylase; AFMID: arylformamidase; AK: adenosine kinase; CD73: cluster of differentiation 73 (5’‐nucleotidase); HAAO: 3‐hydroxyanthranilate 3,4‐dioxygenase; IDO: indoleamine 2,3‐dioxygenase; KMO: kynurenine 3‐monooxygenase; KYNU: kynureninase; NA: nicotinic acid; NADKs: NAD⁺ kinases; NaAD: nicotinic acid adenine dinucleotide; NAD⁺: nicotinamide adenine dinucleotide; NADP⁺: nicotinamide adenine dinucleotide phosphate; NADSYN: NAD⁺ synthase; NAM: nicotinamide; NaMN: nicotinic acid mononucleotide; NAPRT: nicotinate phosphoribosyltransferase; NMN: nicotinamide mononucleotide; NMNH: reduced nicotinamide mononucleotide; NMNAT: nicotinamide mononucleotide adenylyl transferase; NR: nicotinamide riboside; NRH: reduced nicotinamide riboside; NRK: nicotinamide riboside kinase; QPRT: quinolinate phosphoribosyltransferase; SLC: solute carrier transporter; and TDO: tryptophan 2,3‐dioxygenase.

Figure 2. Maintenance of the interorganelle NAD(H) homeostasis

Several pathways and redox systems are involved in the maintenance of cellular NAD(H) homeostasis. The NAD⁺ precursors tryptophan, nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) are transported into the cell via specific transporters or simple diffusion and incorporated into the cytosolic or nuclear NAD⁺ pools. Via the reactions of the cytosolic dehydrogenases or the malate‐aspartate shuttle, NAD⁺ and NADH can then be interconverted to maintain the cytosolic and nuclear NAD⁺:NADH ratios. Inside mitochondria, the malate‐aspartate shuttle works in combination with the TCA cycle and the electron transport chain (ETC) to maintain this redox balance. Besides, the mitochondrial NAD(H) pool is maintained by salvage pathways and active NAD⁺ transport through the newly discovered transporter SLC25A51. ETC: electron transport chain; GAPDH: glyceraldehyde 3‐phosphate dehydrogenase; LDH: lactate dehydrogenase; and PHGDH: phosphoglycerate dehydrogenase.

Figure 3. Mutations in NAD⁺ biosynthesis‐related genes cause a variety of clinical manifestations

Impaired tryptophan transport through defects in the SLC6A19 transporter is manifested as skin lesions and dementia. Dementia is also present in patients with mutations in the HAAO gene. Impairment of NAD⁺ synthesis, either at its upstream enzymes (HAAO and KYNU) or in the distal part of the pathway (NADSYN1), leads to cardiac, renal, hearing, or skeletal (malformations) disorders. Mutations in NMNAT1 are the only known cause for retinal pathology associated with NAD⁺ deficiency in humans.

Figure 4. NAD(P)HX production and repair systems

Via the activity of GAPDH or spontaneously under mild acidic conditions or high temperatures, NADH and NADPH can be hydrated to the R or S forms of their toxic metabolites NAD(P)HX, which can be irreversibly converted to cyclic NAD(P)HX. To avoid the accumulation of these potentially harmful intermediates, R‐NAD(P)HX are epimerized to their S forms through the activity of NAXE. S‐NAD(P)HX is then detoxified to NAD(P)H via the ATP‐dependent activity of NAXD.