Is Nicotinamide Adenine Dinucleotide a Super Supplement or a Hype?



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NAD, or nicotinamide adenine dinucleotide, probably does not need to be presented. With its main alter-egos NADH, NADP and NADPH, our private suite of pyridine-based nucleotides serve as hydride donors in some 400 enzymatic reactions throughout the body. Beyond these characteristic dehydrogenase, hydroxylase and reductase reactions, other members of the larger NAD ecosystem function in receptor signaling pathways. In addition, the NAD backbone of the backbone itself is widely deployed in DNA repair, and directly consumed as an addition to many other important molecules in different organelles.

Precursors and derivatives of NAD now adorn drugstore and supermarket shelves everywhere. These species include not only classical niacin (vitamin B3), but also other generally abbreviated forms simply NA, NAM, NMN or NR. But what exactly are these molecules and what, if anything, could they do for us?

The concentrations of NAD throughout the body reflect a delicate balance between synthesis, consumption, transport and transformation. While NAD is created de novo from niacin using the so-called Preiss-Handler pathway in organs such as the liver or kidneys, many other tissues, such as the nervous system, rely on recovery pathways using nicotinamide. Delivery of an appropriate bolus of NAD to the many distant synaptic locations of a neuron is provided by motile mitochondria. While NAD has been studied for almost 100 years, it was not until last September that the identity of the specific transporter that pumps NAD into mitochondria, SLC25A51, was officially discovered.

NAD is consumed through the efforts of at least three different classes of enzymes: poly ADP-ribose polymerases (PARP), NAD-dependent deacetylases (SIRTUINS) and NADases such as CD38. This last molecule, CD38, is the subject of an avalanche of articles recently published with great fanfare in Nature’s metabolism. Taking a clue from previous findings that as the body ages NAD dramatically decreases and CD38 increases, these studies were able to collectively link these two processes in a direct causal relationship.

The first article, by Chini et al., Demonstrates that the expression of CD38 in macrophages induced by inflammation associated with senescence is, in fact, the reason for the age-related decline of NAD. From the summary, the second article, by Covarrubias et. al., seems to show roughly the same; however, the generally reliable Sci-Hub had difficulty loading this paper.

The canonical function of CD38 has traditionally been attributed to the generation of a cyclic derivative of NAD known as cADPR. This function is vaguely reminiscent of the cyclases directed by the G protein receptor which envelop purine nucleotides in their cyclic forms. Moreover, when nicotinic acid is present under acidic conditions, CD38 can also hydrolyze NADP to NAADP. Depending on how you look at it, CD38 is either terribly ineffective at retaining NAD or very effective at liquidating it. It has been estimated that 100 molecules of NAD are required to generate a single molecule of cADPR. Ineffectiveness appears to be the rule in NAD systems, as researchers have determined that to make one gram of niacin from tryptophan, around 67 mg of the amino acid is needed.

A curious feature of CD38 is its unexplained paradoxical membrane topology. In other words, most of the enzyme is configured in a type II membrane orientation with its catalytic domain facing the extracellular compartment functioning as an ecto-NAD glycohydrolase. How, then, does it apparently control intracellular levels of NAD and calcium stores inside the cell? The answer, provided by Chini et. al., is that it bypasses all of the works via the extracellular degradation of the NAD precursor NMN.

In addition to CD38 type II, there is also a type III version whose catalytic domain faces the cytosol. Cytosolic access is activated either by having an upside-down orientation in the plasma membrane or by persisting in the submembrane system of the cell. CD38 type III is an unglycosylated protein and differs from type II in that a disulfide bond is not formed in its carboxyl-terminal residues. Antibodies like M19 can therefore be specifically designed to recognize it. The protein itself is activated by crosslinking another set of cysteines found at positions 164 and 177. An enzyme of the NAD family called NADPH-diaphorase 4 (Nox4) is responsible for this activation. It generates H2O2, which then facilitates crosslinking.

Is the CD38 really the Boogeyman it was designed to be?

CD38 has another cellular function, and in some ways more fascinating: it is moonlighted as the master coordinator of mitochondrial transfer between cells. A few years ago, Stuart Rushworth and his colleagues discovered that leukemia blast cells (AML) are able to survive and proliferate by forcing local stem cells in the bone marrow to feed them with functioning mitochondria through tiny filaments called tunnel nanotubes. AML cells do this by generating a diffusible superoxide from another Nox enzyme, this time a Nox2. While blocking this transfer may appear to be a potential way to treat cancers, Nox2 inhibitors are not clinically available, and even if they were, blocking critical Nox signaling can be fatal in itself.

In the meantime, Hayakawa et. Al. Discovered that in vivo, astrocytes use a CD38-based mechanism to package mitochondria in vesicles for transfer to neurons. This process allows neurons to survive difficult times, especially a stroke. So maybe CD38 isn’t all bad. In other words, like cortisol, it can sometimes betray the body when strained too high in specific places, but some basic presence may be necessary for normal daily functioning.

Realizing these findings, Rushworth’s group later discovered that high expression of CD38 in their liquid tumor blood cells caused similar mitochondrial transfer and the rescue of these bad actors. Clinical trials in multiple myeloma are currently underway to assess the merits of CD38 antibodies such as isatuximab, which directly induces apoptosis, and daratumumab, which indirectly induces apoptosis. The new antibodies of Nature’s metabolism the articles above may also be helpful here.

But what about neurons, do they have CD38? Do they donate mitochondria?

The surprising discovery of the existence of another enzyme that produces cADPR and NAADP in neurons has not gone unnoticed. In this case, it was not CD38, but rather a molecule that has a completely different sequence. Known as SARM1, for “containing an α motif and sterile armadillo”, it is a conserved member of the Toll-like receptor family and appears to regulate axonal degeneration. Of particular interest, SARM1 has a unique localization sequence that targets it to the mitochondria, where it has been associated with apoptosis.

Until recently, it was believed that neurons only got rid of old or weak mitochondria. By ejecting worn out mitochondria from their axons, apoptosis or other types of general discomfort would likely be avoided. This type of externalized mitophagy has in particular been discovered in retinal ganglion cells where the mitochondria have been absorbed by astrocytes and have been shown to be degraded in LAMP1 positive inclusions (lysosomal associated protein). However, more recent studies have shown that the altruistic donation of healthy mitochondria by neurons is really one thing, despite many skeptics and nondescript people out there. Using a co-culture system, Gao et. Al recently showed that astrocytes were able to increase the net membrane potential of their local mitochondrial stock by acquiring healthy reinforcements from neighboring neurons. To do this, either CD38 or one of the two proteins called MIRO was needed.

MIRO proteins adapt mitochondria to the motor proteins that transport them along the filaments of the cytoskeleton. The authors also showed that this process breaks down into a condition known as Alexander disease (AxD). In AxD, astrocytes have a defect in their code for GFAP (glial fibrillary acid protein), a member of the intermediate family of cytoskeletal proteins. Mitochondria that are transferred to normal individuals are not degraded in LAMP-positive lysosomes and persist as highly functioning members within the mitochondrial network of their new hosts. This is the first case of a major disease whose cause can be directly attributed to a deficit in mitochondrial transfer.

Numerous studies have suggested that the NADH / NAD ratios in mitochondria and NADPH / NADP in the cytosol are the overall indicators of the state of the cell as a whole. Adding mitochondrial transfer to the mix offers many new ways to interpret how cells and organs adapt to maintain the required tolerances based on NAD. CD38 in particular represents both an attractive new therapeutic opportunity and a unique insight into behind-the-scenes cooperation between cells.


Chronic inflammation leads to reduced NAD +


More information:
Claudia CS Chini et al. The ecto-enzyme CD38 in immune cells is induced during aging and regulates the levels of NAD + and NMN, Nature’s metabolism (2020). DOI: 10.1038 / s42255-020-00298-z

Anthony J. Covarrubias et al. Senescent cells promote tissue decline of NAD + during aging via the activation of CD38 + macrophages, Nature’s metabolism (2020). DOI: 10.1038 / s42255-020-00305-3

© 2020 Science X Network

Quote: NAD: Is Nicotinamide Adenine Dinucleotide a Super Supplement or a Hype? (2020, December 4) retrieved December 4, 2020 from https://phys.org/news/2020-12-nad-nicotine-adenine-dinucleotide-super.html

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