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NAD+ Metabolism and Retinal Degeneration (Review)

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NAD+ Metabolism and Retinal Degeneration (Review) EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 670, 2021 NAD+ metabolism and retinal degeneration (Review) ANDREEA SILVIA PÎRVU1*, ANA MARINA ANDREI2, ELENA CAMELIA STĂNCIULESCU2*, ILEANA MONICA BANIȚĂ3, CĂTĂLINA GABRIELA PISOSCHI2*, SANDA JURJA4* and RADU CIULUVICA5 1Department of Biochemistry, Faculty of Medicine; 2Department of Pharmaceutical Biochemistry, Faculty of Pharmacy; 3Department of Histology, Faculty of Dentistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova; 4Department of Ophthalmology, Faculty of Medicine, ‘Ovidius’ University of Constanta, 900527 Constanta; 5Faculty of Dentistry, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania Received February 12, 2021; Accepted March 16, 2021 DOI: 10.3892/etm.2021.10102 Abstract. The recent years has revealed an intense interest in 3. Diet and NAD+ level the study of nicotinamide adenine dinucleotide (NAD+), partic‑ 4. NAD+ and diseases ularly in regards to its intermediates, such as nicotinamide and 5. NAD+ in normal and abnormal function of the retina nicotinic acid known as niacin, and also nicotinamide riboside. 6. Conclusions Besides its participation as a coenzyme in the redox transfor‑ mations of nutrients during catabolism, NAD+ is also involved in DNA repair and epigenetic modification of gene expres‑ 1. Introduction sion and also plays an essential role in calcium homeostasis. Clinical and experimental data emphasize the age‑dependent Nicotinamide adenine dinucleotide (NAD+) is considered the decline in NAD+ levels and its relation with the onset and precursor for the pyridine nucleotide family constituted by progression of various age‑related diseases. Maintaining NADH and two phosphorylated forms, nicotinamide adenine optimal levels of NAD+ has aroused a therapeutic interest in dinucleotide phosphate in its oxidized (NADP+) and reduced such pathological conditions; NAD+ being currently regarded (NADPH) forms (1). All of these nucleotides are well‑known as an important target to extend health and lifespan. Based on cofactors in numerous cellular processes. NAD+ is the a systematic exploration of the experimental data and literature substrate for major redox transformations of nutrients during surrounding the topic, this paper reviews some of the recent the catabolic phase of metabolism. Its reduced form, NADH, is research studies related to the roles of the pyridine nucleotide the main source of electrons for mitochondrial oxidative chain family focusing on biosynthesis, NAD+ deficiency‑associated and production of adenosine triphosphate through oxidative diseases, pathobiochemistry related to retinal degeneration phosphorylation. NAD+ is also involved in DNA repair, as and potential therapeutic effects on human vision as well. a substrate for poly(ADP‑ribose) polymerases (PARP) (2), epigenetic modification of gene expression, also having an important influence on immunological function (3). NAD+ Contents also has a critical role in calcium homeostasis, as the substrate for NAD+ glycohydrolases, enzymes related to the production 1. Introduction of cyclic ADP‑ribose, a calcium efflux effector (4). 2. NAD+ biosynthesis, metabolism and effects on the Since the original discovery of NAD+ by Harden and human body Young in 1906 in cell‑free yeast juices as a factor that enhanced the rate of fermentation, many studies have been developed to reveal the NAD+ biosynthetic pathway as a key player in cellular metabolism (5). NAD+ is currently regarded as an important target with which to extend lifespan and health Correspondence to: Dr Ana Marina Andrei, Department of span. Accurate evaluation of the NAD+ metabolome is of great Pharmaceutical Biochemistry, Faculty of Pharmacy, University interest due to its association with cognitive impairment, of Medicine and Pharmacy of Craiova, 2‑4 Petru Rareș Street, cancer, normal aging and age‑related disorders (1). 200349 Craiova, Romania Research conducted to date has elucidated E‑mail: [email protected] the signaling pathways and cellular processes that *Contributed equally contribute to the maintenance of pyridine nucleoside and nucleotide homeostasis; the regulation of molecular Key words: pyridine nucleotide family, NAD+, niacin, nicotinamide mechanisms underlying NAD+ metabolism is known but riboside, retinal degeneration, NAD+ therapeutic target the use of its precursors in therapy are still incompletely explained. 2 PÎRVU et al: NAD+ METABOLISM AND RETINAL DEGENERATION 2. NAD+ biosynthesis, metabolism and effects on the regarding pyridine nucleotide metabolism in eye structures human body and its involvement in visual dysfunctions are scarce. NAD+ biosynthesis in mammals involves five important inter‑ 3. Diet and NAD+ level mediates including tryptophan, niacin, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), through Dietary supplementation is the only way to increase body three biosynthetic pathways: i) Nucleotide salvage from nico‑ NAD+ levels. Since NAD+ administration is not efficient tinamide (NAM), NR and NMN; ii) de novo synthesis from enough to increase NAD+ levels, its precursors, such as NAM tryptophan and iii) Preiss‑Handler pathway from nicotinic and NA known as niacin, NMN and NR could be useful to acid (NA) (6). increase NAD+ levels in animal models and humans (18). In mammals, the salvage pathway is the major route to Most raw foods provide these substances which can generate NAD+. Conversion of NMN, one of the forms of the regulate cellular activities and the timing of changes that water‑soluble vitamin B3, to NAD+ is catalyzed by nicotin‑ lead to aging phenotypes (13). Another important precursor amide mononucleotide adenylyltransferase (Nmnat) (Fig. 1). of NAD+ is the amino acid tryptophan which is synthetized NMN can be synthesized by nicotinamide phosphoribosyl‑ via the kynurenine pathway. While NR is the form of vitamin transferase (Nampt) from NAM. Bieganowski and Brenner B3 found in humans and cow milk and other foods, NA is revealed an alternative NAD+ salvage biosynthesis pathway, produced by plants and algae, and tryptophan is the most in which NR, another form of vitamin B3 that enters cells abundant amino acid found in animal and plant proteins (19). through nucleoside transporters, could be converted to NAD+ Many of the biochemical studies performed recently have by nicotinamide riboside kinases (NMRK1 and NMRK2) and shown that a poor diet lacking niacin and tryptophan intake or a Nmnat via phosphorylation reactions (7). chronic immune activation can lead to inefficient production of In recent years, NMN and NR have been extensively NAD+, where catabolism exceeds anabolism producing a conse‑ investigated in various experiments on rodents and humans quent cellular dysfunction (20). By contrast, a reduced energy and evidence suggests that with age NAD+ levels decline load due to activities such exercise, calorie restriction, fasting and at a systemic level (8,9), causing profound metabolic glucose deprivation can increase the concentration of NAD+ (8). changes (10). These precursors of NAD+ have an essential Although studies on rodents have shown that both NMN influence on the elevation of NAD+ concentration in a variety and NR enhance NAD+ biosynthesis and have beneficial of tissues, automatically suggesting a beneficial therapeutic effects in multiple disorders (21‑23), it still remains unclear effect (8,11,12). what mechanisms mediate their beneficial effect. Presently, The metabolic balance of NAD+ in the cellular environ‑ the pharmacokinetics and metabolic fates of NAD+ precursors ment can be accomplished in several ways and involves are still under investigation, multiple human clinical trials multiple metabolites in an oxidized and reduced form such being conducted to study and understand the safety of NAD+ as NADP+, NADH, NADPH, and nicotinic acid adenine precursor supplementation, mainly NR and NMN (24‑26). dinucleotide phosphate (NAADP), all with an essential role The concentrations of NAD+ and NAM in blood are in the in energy production and cellular metabolism, acting as one micromolar range and can be boosted by oral administration of proton‑accepting or donating coenzymes. NAD+ derivatives their precursors, NR and NMN. In their study, Trammell et al are important for regulating cellular redox status, intracellular showed that a daily dose of 1000 mg NR leads to a 2.7‑fold Ca2+ pools, DNA damage and repair, cell cycle timing and rise in blood NAD+ after one dose of NR (24). Another clinical lipid and energy metabolism (13). NAD+ is a major cofactor study demonstrated that daily doses of NR up to 1000 mg are for mitochondrial ATP production and for NAD‑dependent well tolerated and efficient to increase NAD+ levels by almost enzymes including sirtuins and poly‑ADP‑ribosylpolymerases, 60% in peripheral blood mononuclear cells (25). Irie et al essential players in fundamental processes such as cell divi‑ conducted a human study regarding the safety of a single oral sion and proliferation, apoptosis, aging, senescence and stress NMN dose (100, 250 or 500 mg) in healthy Japanese men resistance (14). Lin and Guarente argued that sirtuins can by investigating the pharmacokinetics of NMN metabolites sense the NADH/NAD+ ratio in cells by the recognition of the for 5 h after each intervention and found that NMN supple‑ oxidized dinucleotides, but it seems that other cellular factors mentation is safe without causing any significant deleterious also respond to the alterations within NADH levels (15). effects (27). For many years
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