Cellular and Mitochondrial NAD Homeostasis in Health and Disease

Abstract

The mitochondrion has a unique position among other cellular organelles due to its dynamic properties and symbiotic nature, which is reflected in an active exchange of metabolites and cofactors between the rest of the intracellular compartments. The mitochondrial energy metabolism is greatly dependent on nicotinamide adenine dinucleotide (NAD) as a cofactor that is essential for both the activity of respiratory and TCA cycle enzymes. The NAD level is determined by the rate of NAD synthesis, the activity of NAD-consuming enzymes, and the exchange rate between the individual subcellular compartments. In this review, we discuss the NAD synthesis pathways, the NAD degradation enzymes, and NAD subcellular localization, as well as NAD transport mechanisms with a focus on mitochondria. Finally, the effect of the pathologic depletion of mitochondrial NAD pools on mitochondrial proteins' post-translational modifications and its role in neurodegeneration will be reviewed. Understanding the physiological constraints and mechanisms of NAD maintenance and the exchange between subcellular compartments is critical given NAD's broad effects and roles in health and disease.

Keywords: NAD; brain; mitochondria.

Figure 1

Metabolic pathways of NAD biosynthesis and NAD degradation. The main source of NAD is from the salvage pathway, where it is generated by enzymatic reactions that use nicotinamide (Nam) to generate nicotinamide mononucleotide (NMN) via nicotinamide phosphotransferase (NAMPT) activity. The NMN can also be formed by phosphorylation of nicotinamide riboside (NR) via NR kinase (NRK). NMN is then converted to NAD by nicotinamide mononucleotide adenylyl transferase (NMNAT). In the Preiss–Handler pathway, nicotinic acid adenine dinucleotide (NAMN) is synthesized from nicotinic acid (NA). Subsequently, NAMN is converted by NMNAT into nicotinic acid adenine dinucleotide (NAAD), which is then amidated to NAD by NAD synthetase (NADS). De novo pathway starts from tryptophane (Trp), and also leads to formation of NAMN by conversion from quinolinic acid (QA). NAD is consumed during poly-ADP-ribosylation or acetylation of proteins driven by PARP or sirtuins. Additionally, NAD is used as substrate by CD38 and SARM1 enzymes.

Figure 2

Schematic illustration of NAD and NADH molecules and their charges. Although the abbreviation for nicotinamide adenine dinucleotide is written with a plus sign (NAD⁺), its net charge is negative due to the presence of two phosphate groups. Similarly, NADH has a net charge of negative two.

Figure 3

Mitochondrial NAD transporter in plants and yeast (A), and in mammalian cells (B). In plants and yeast mitochondria NAD is transported from cytosol to the mitochondrial matrix for exchange with ADP or AMP. Mammalian transporter SLC25A51 is specific for NAD; however, it is not known whether it works as a co-transporter and which metabolite is exchanged for NAD. NAD⁻ is shown with one net negative charge (see Figure 2). The exchange for ADP³⁻ or AMP²⁻ in plant and yeast mitochondria is driven by their concentration gradient and the mitochondrial membrane potential (ΔΨ).