NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns

Abstract

In the twentieth century, NAD+ research generated multiple discoveries. Identification of the important role of NAD+ as a cofactor in cellular respiration and energy production was followed by discoveries of numerous NAD+ biosynthesis pathways. In recent years, NAD+ has been shown to play a unique role in DNA repair and protein deacetylation. As discussed in this review, there are close interactions between oxidative stress and immune activation, energy metabolism, and cell viability in neurodegenerative disorders and ageing. Profound interactions with regard to oxidative stress and NAD+ have been highlighted in the present work. This review emphasizes the pivotal role of NAD+ in the regulation of DNA repair, stress resistance, and cell death, suggesting that NAD+ synthesis through the kynurenine pathway and/or salvage pathway is an attractive target for therapeutic intervention in age-associated degenerative disorders. NAD+ precursors have been shown to slow down ageing and extend lifespan in yeasts, and protect severed axons from degeneration in animal models neurodegenerative diseases.

Figure 1.

NAD⁺ metabolism in higher eukaryotes. The de novo pathway represents the catabolism of the amino acid l-tryptophan to quinolinic acid through the KP. Quinolinic acid is then converted to nicotinic acid mononucleotide (NaMN) which connects to the salvage pathway. The three different salvage pathways start either from nicotinamide (Nam), nicotinic acid (Na), or nicotinamide riboside (NR). Nicotinamide is a by-product of NAD metabolism which gets converted into nicotinamide mononucleotide (NMN by nicotinamide phosphoribosyl transferase (NamPRT)) and then into NAD by the action of nicotinamide mononucleotide adenylyl transferases (Na/NMNAT1, 2, and 3).

Figure 2.

Formation of lipid hydroperoxides. A great variety of compounds are formed during lipid peroxidation of membrane phospholipids.

Figure 3.

Phosphorylation of H2AX at Serine 139 following ROS damage to DNA. Under mild-to-moderate oxidative damage, phosphorylation of H2AX can lead to temporary cessation of cellular function and DNA repair. However, under extreme conditions, hyperphosphorylation of H2AX can lead to cell death via an apoptotic mechanism.

Figure 4.

Schematic representation of poly(ADP-ribose) synthesis. Poly(ADP-ribose) polymerases breaks the bond between nicotinamide and ribose in NAD⁺ leading to the formation of ADP-ribosyl moiety. Repeated reaction triggers the formation of PAR chains.

Figure 5.

PARP-1-dependent signalling in apoptosis. Excessive oxidative stress leads to hyperactivation of PARP-1 in the nucleus. PAR formation and NAD⁺ depletion can trigger a cascade of events which can lead to the release of apoptotic inducing factor (AIF). AIF can migrate to the nucleus where it can trigger cell death. AIF can also promote release of cytochrome c (cyt c) through upregulation of Beclin-2 protein (Bcl-2) which can cause apoptosis via a downstream signalling through caspase activation.

Figure 6.

Sirtuin enzymatic activities. Sirtuins display two different NAD⁺ consuming activities, both of which render NM as a product.

Figure 7.

NAD⁺/nicotinamide levels may serve as converging points for interaction of PARP-1 and SIRT1 pathways. It is conceivable that poly(ADP-ribose) metabolism can downregulate SIRT1 through NAD⁺ depletion and nicotinamide production during oxidative stress. Reciprocally, regulation by SIRT1 deacetylation for expressing genes related to apoptosis or longevity may depend on PARP-1 activity. PARP-1 inhibitors maintain NAD⁺ levels and suppress the nicotinamide surge, and therefore may indirectly serve as SIRT1 enhancers. The interactions of PARP-1/SIRT1 pathways provide a network for multicellular eukaryotes to effectively deal with nutritional supply and oxidative stress.