The concept of “NAD+ current”

The concept of “NAD+ current” is even more complicated than the “ATP current.” This is because NAD+ cannot penetrate the inner mitochondrial membrane.

NAD+ is regenerated in the cytoplasm by a number of distinct reactions such as: pyruvate -> lactate, oxaloacetate -> malate, dihydroxyacetone phosphate -> glycerol phosphate.

In the malate-aspartate shuttle, the malate alpha-keto-glutarate antiporter exports alpha-keto-glutarate from mitochondria and carries malate into the mitochondria, where oxaloacetate is regenerated along with NADH. Oxaloacetate plus glutamate are converted to aspartate and alpha-keto-glutarate. Aspartate is transported to the cytoplasm while glutamate is transported into the mitochondria. In the cytoplasm aspartate and alpha-keto-glutarate are converted to oxaloacetate plus glutamate. The sum total of all of these reactions is cyto-NADH + mit-NAD+ -> cyto-NAD+ + mit-NADH. It looks as if cytoplasmic NADH was converted back to NAD+ by transport into mitochondria, oxidation, and then re-importation, when in fact cyto-NADH never went into mitochondria and mitochondrial NAD+ never came out.

The glycerol phosphate shuttle carries glycerol phosphate into the mitochondria, where dihydroxyacetone phosphate is regenerated along with FADH2, which is used to reduce ubiquinone. The NADH in the mitochondria is oxidized to NAD+ in the OXPHOS steps, even when ATP is not being made at any significant rate.

These shuttles are key components of the NAD+ current. When total NAD+ is low, as in nicotinamide dietary deficiency without supplementation, the NAD+ current is unusually low, and the cytoplasmic metabolism backs up at key points, leading to trouble.

Some backups that lead to trouble:

1. When intracellular glucose is very high (and after a high sugar meal or dessert, it can get extremely high in tissues not requiring insulin for uptake, such as neural tissues, the retina, and kidneys), hexokinase is overwhelmed, and some glucose is converted to sorbitol, and then it is dependent on the NAD+ current to continue to fructose, and from there to fructose-6-phosphate by hexokinase, which is already overwhelmed by excess glucose. Thus when intracellular glucose is very high and nicotinamide is deficient, sorbitol builds up. Temporarily this probably leads to export of key osmolytes like taurine and/or inositol, and the consequences of their intracellular decreased concentrations are probably not negligible. One consequence is that since taurine is needed to balance intracellular sodium, potassium, magnesium, and calcium – temporary intracellular cation imbalances and their sequelae are predicted.

Another possible longer term consequence of the export of taurine and/or inositol is deficiency in either or both. Every molecule that is excreted will eventually become part of the kidney filtrate and is at risk of being lost to urine, especially if there are also problems with reabsorption, as in diabetics. Are diabetics deficient in taurine and/or inositol? Would not be surprising if they were.

As the excess sugar is disposed of as glycogen, as lactate (which is excreted), but which also comes back from the liver and kidneys as glucose, as fat, as carbon dioxide and water (with whatever mitochondrial respiration is still working), the sorbitol to fructose reaction will accelerate, and the other osmolytes, given possible deficiencies, will come back into the cell to the degree that they can, restoring some balance, and better cation flow. But what were the consequences during the (prolonged?) overwhelming of hexokinase?

2. The glyceraldehyde-3-P to 1,3-diphosphoglycerate reaction backs up when NAD+ current is too low, and this leads to increased methylglyoxal, and to increased advanced glycation end products. The deleterious effects are pretty obvious with this deceleration in the NAD+ current.

It seems sensible to supplement nicotinamide because the NAD+ current can limit the effectiveness of the vitamin, even when the cell is maintaining the proper ratio of NAD+/NADH in each compartment.

When supplemented, is nicotinamide usually normalized to near its maximum total concentration? Are there still cases where the total rates of reaction of the enzymes that consume NAD+ exceed the total rates of reaction of the enzymes that regenerate NAD+, and this becomes rate limiting for the NAD+ current, even though the absolute, formal concentration of [NAD+] + [NADH} is now near maximal?

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