Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Abstract

Significance: Nicotinamide adenine dinucleotide (NAD⁺) participates in redox reactions and NAD⁺-dependent signaling processes, which involve the cleavage of NAD⁺ coupled to posttranslational modifications of proteins or the production of second messengers. Either as a primary cause or as a secondary component of the pathogenic process, mitochondrial dysfunction and oxidative stress are prominent features of several neurodegenerative diseases. Activation of NAD⁺-dependent signaling pathways has a major effect in the capacity of the cell to modulate mitochondrial function and counteract the deleterious effects of increased oxidative stress. Recent Advances: Progress in the understanding of the biological functions and compartmentalization of NAD⁺-synthesizing and NAD⁺-consuming enzymes have led to the emergence of NAD⁺ metabolism as a major therapeutic target for age-related diseases.

Critical issues: Three distinct families of enzymes consume NAD⁺ as substrate: poly(ADP-ribose) polymerases (PARPs), ADP-ribosyl cyclases (CD38/CD157) and sirtuins. Two main strategies to increase NAD⁺ availability have arisen. These strategies are based on the utilization of NAD⁺ intermediates/precursors or the inhibition of the NAD⁺-consuming enzymes, PARPs and CD38. An increase in endogenous sirtuin activity seems to mediate the protective effect that enhancing NAD⁺ availability confers in several models of neurodegeneration and age-related diseases.

Future directions: A growing body of evidence suggests the beneficial role of enhancing NAD⁺ availability in models of neurodegeneration. The challenge ahead is to establish the value and safety of the long-term use of these strategies for the treatment of neurodegenerative diseases. Antioxid. Redox Signal. 28, 1652-1668.

Keywords: CD38; NAD; PARP; mitochondria; neurodegeneration; oxidative stress.

FIG. 1.

NAD⁺ as an electron carrier. In redox reactions, a hydride equivalent is reversibly transferred at the nicotinamide moiety causing a switch between oxidized (NAD⁺) and reduced (NADH) forms of the dinucleotide.

FIG. 2.

NAD⁺-consuming reactions. (A) NAD⁺ hydrolysis is coupled to deacetylation reactions by sirtuins. (B) Cyclic ADP-ribose production by ADP-ribosyl cyclases, including CD38 and CD157. (C) PARPs catalyze the addition of ADP-ribose to an acceptor protein following with extension and branching of the chain to form poly(ADP-ribose) polymers. Member of this family may also have mono-ADP-ribosylation activity, catalyzing the transfer of a single ADP-ribose moiety to the acceptor protein. All three reactions produce nicotinamide as a by-product. PARP, poly(ADP-ribose) polymerase.

FIG. 3.

Subcellular localization, enzymatic activity, and selected substrates of the seven mammalian sirtuins. SIRT1, SIRT6, and SIRT7 localize to the nucleus, SIRT2 is cytoplasmic, and SIRT3, SIRT4, and SIRT5 are mitochondrial. SIRT1 and SIRT2 may shuttle between their respective compartments. See the text for ANT, adenine nucleotide translocator; G6PD, glucose-6-phosphate dehydrogenase; GABPβ1, GA repeat binding protein beta 1; GDH, glutamate dehydrogenase; IDH2, isocitrate dehydrogenase 2; LCAD, long chain acyl-CoA dehydrogenase; NDUFA9, NADH:ubiquinone oxidoreductase subunit A9; NRF, nuclear respiratory factor; OPA1, optic atrophy 1; PDH, pyruvate dehydrogenase; PGAM-1, phosphoglycerate mutase-1; PGC-1?, peroxisome proliferator-activated receptor coactivator-1?; SIRT, sirtuin; SOD, superoxide dismutase; SREBP1, sterol regulatory element binding protein 1.

FIG. 4.

NAD⁺ biosynthetic pathways in mammals. Four building blocks may be used for NAD⁺ synthesis: L-tryptophan, NA, NR, and NAM. The de novo pathway uses L-tryptophan to generate, through several intermediate steps, quinolinate. Quinolinate is sequentially converted to NAMN, NAAD, and NAD⁺ by the action of QPRT, NMNATs, and NADS, respectively. In the Preiss-Handler pathway, NAPRT converts NA to NAMN, which is then used by NMNATs. NR can enter the salvage pathway either by the action of NRK, which generates NMN, or by the reaction catalyzed by PNP, which generates NAM. NAM is subsequently converted to NMN by NAMPT, the rate-limiting step in the salvage pathway. NRKs can also convert NAR to NAMN. All the biosynthetic pathways converge at the level of dinucleotide formation catalyzed by the NMNATs. NMNATs use NAMN and NMN with similar efficiency. NAD⁺-consuming reactions catalyzed by PARPs, CD38, and sirtuins release NAM that may be use to resynthesize NAD⁺ in the salvage pathway. NA, nicotinic acid; NAD⁺, nicotinamide adenine dinucleotide; NAAD, nicotinic acid adenine dinucleotide; NADS, NAD⁺ synthetase; NAM, nicotinamide; NAR, nicotinic acid riboside; NR, nicotinamide riboside; NRK, NR kinase; NMN, nicotinamide mononucleotide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyl transferase; PNP, purine nucleoside phosphorylase; QPRT, quinolinate phosphoribosyltransferase.

FIG. 5.

Compartmentalization of NAD⁺ synthesis and utilization. NMN and NR effectively increase total and mitochondrial NAD⁺. No NMN or NAD⁺ transporters have been identified in mammalian cells. CD73 dephosphorylate NMN to produce NR, which is then imported into the cell, probably by ENTs. Mitochondria can synthesize NAD⁺ from NMN, but transport of cytoplasmic NAD⁺ into the mitochondria also appears to contribute to the mitochondrial NAD⁺ pool. NAD⁺ is consumed intracellularly by PARPs and sirtuins, although CD38 has also been found in the endoplasmic reticulum and in the nuclear and mitochondrial membranes (not shown). NAD⁺ can also be transported outside of the cell, likely through connexin 43 hemichannels (30). CD38 and CD157 consume extracellular NAD⁺. Cells can also synthesize NAD⁺ from nicotinic acid and tryptophan (Fig. 4). Dashed lines and question marks indicate steps for which the exact mechanism has not been fully characterized. ENT, equilibrative nucleoside transporter.

FIG. 6.

Possible protective mechanisms responsible for the neuroprotection conferred by increasing NAD⁺ availability. Supplementation with NAD⁺ precursors/intermediates (NMN and NR) or inhibition of NAD⁺-consuming enzymes (PARP1 and CD38) leads to increased NAD⁺ availability and sirtuin activity. PARP1 inhibition could have additional effects not depicted in the figure (see NAD⁺-dependent signaling section for details).