Exogenous Nucleotides, Glycolysis, Cytosolic NADH, and the Tricarboxylic Acid Cycle

What I was getting at with the potential effect of a ribose-5-phosphate-induced (via uridine-derived ribose-1-phosphate) increase in the cytosolic NADH/NAD+ ratio, in response to the entry of ribose-5-phosphate into the nonoxidative pentose cycle (which the ribose-5-phosphate, in the azide-treated cells, would probably not remain in but rather be converted en masse into glycolytic substrates), was that, in the presence of a complex IV inhibitor like sodium azide, the increase in cytosolic NADH would tend to indirectly inhibit, rather than support, the activities of the mitochondrial enzymes of the tricarboxylic acid cycle (and the gluconeogenic, mitochondrial methylmalonate semialdehyde dehydrogenase).

That was sort of the upshot of those articles on ribose, and it's relevant to the mechanisms of neuroprotection by uridine. The idea of those articles was that the increases in the cytosolic NADH/NAD+ ratio, induced by reducing sugars and by glycolysis in general, would be beneficial as long as the cells, in which the accelerated glycolytic activity was occurring, were either near to or in cells with a high oxidative capacity. If oxidative phosphorylation is being inhibited, the extra NADH can indirectly inhibit the activities of tricarboxylic acid cycle enzymes via the malate-aspartate shuttle that indirectly transfers reducing equivalents from the cytosol to the mitochondria.

I think that's part of the reason the research on ribose seems to mainly be on cardiac myocytes and myocytes in skeletal muscles. Those cell types (and ribose was shown to act mainly on the highly-oxidative muscle fibers) have very high oxidative capacities, very high mitochondrial contents. It's as if there's some problem with the mechanisms that would normally stimulate glycolysis, and stimulating it, so to speak, artificially, with exogenous ribose or ribose-1-phosphate, only "works" when there are abundant and functional mitochondria nearby, basically. I remember reading that, for some reason, glycolysis can become shut down in cardiac myocytes following ischemia, but the tremendous oxidative capacity (like 30 percent of the cytosolic volume is mitochondria in cardiac myocytes, in some cases) is there and has not necessarily been irreparably damaged by transient ischemia. I'll try to find that article.

That might be one of the issues with treating chronic mitochondrial disorders with uridine alone. Purines and pyrimidines have sometimes been shown to elevate lactate output in cell culture studies, and ribose definitely has. So there's probably some kind of balancing act, whereby exogenous nucleotides are beneficial but can conceivably elevate the lactate/pyruvate ratio in cells whose oxidative capacity has become diminished or otherwise disturbed.