Cytosolic Redox State and the TCA Cycle

This is the type of thing that I was talking about. An increase in the cytosolic NADH/NAD+ ratio per se can reduce the activities of the mitochondrial TCA cycle enzymes. This occurs because the increase in the cytosolic NADH/NAD+ ratio can disrupt the levels of intramitochondrial TCA cycle substrates, via the malate-aspartate shuttle that allows the cytosolic redox state to be reflected in the mitochondrial NAD+/NADH ratio, and thereby inhibit oxidative phosphorylation. That inhibition of the TCA cycle can then, in turn, interfere with the capacity of mitochondrial activity to support the cytoplasmic redox state via the malate-aspartate shuttle.

The authors talk about the way this doesn't normally occur in cardiac myocytes, that lactate is usually oxidized *more readily* in that type of oxidative tissue. But that's the whole issue with mitochondrial disorders. At first glance, it seems that the heart muscle is "oxidative" and wouldn't be amenable to ATP-buffering via glycolysis. But it's as if the oxidative capacity becomes a detriment, turns things upside-down, so to speak, following an ischemic insult:

http://www.ncbi.nlm.nih.gov/pubmed/9737943 (Barron et al., 1998)

But in cardiac myocytes and skeletal muscle myocytes (and CNS neurons, under normal circumstances, presumably, at least in comparison to astrocytes), there can be enough of a "reserve" of oxidative capacity, normally, to prevent that type of increase in the cytosolic NADH/NAD+ ratio, such as during exercise or the like, from just shutting everything down with lactate overload. But it helps explain the fact that, in highly oxidative cells, it's as if mitochondrial function is more essential as a mechanism, via the malate-aspartate shuttle, that helps maintain glycolysis in the cytosol. It helps explain the breakdown of glycolysis in cardiac myocytes (or neurons in the brain) following reperfusion, given that reactive oxygen species (such as NO, which can bind directly to the heme sites on the electron transport chain) would inhibit mitochondrial function and thereby also prevent glycolysis from proceeding normally.

But the issue is that things like enormous-dose uridine, from triacetyluridine or purines, conceivably, can increase lactate production and not get at the underlying deficit in oxidative phosphorylation immediately (in the context of chronic mitochondrial dysfunction). But something like CoQ10 has the potential to just increase the production of reactive oxygen species without addressing the underlying cause of mitochondrial dysfunction (such as mtDNA damage due to oxygen radicals or superoxide, independent of the folate cycle, or due to an increase in the intramitochondrial dUTP/dTTP ratio in response to "network disruptions" in the folate cycle enzymes).