Unanswered Questions in Relation to Uridine as an Approach to Reducing Heteroplasmy

Before I forget to mention this...I forgot to mention that, in the use of uridine to restore respiratory chain dysfunction in the face of ongoing or existing heteroplasmy, researchers had the idea that providing large amounts of uridine (an 80 uM (micromolar) plasma uridine for >12 hrs. of the day) would be the only thing that would allow replication of the mutant mtDNA copies. The basis for that idea is that polymerase-gamma has a high degree of processivity, meaning that it copies the entire genome of a single copy of mtDNA without "pausing." The mutant copies of mtDNA tend to be shorter, because they have large deletions, and they tend to be replicated more quickly and preferentially (http://www.ncbi.nlm.nih.gov/pubmed/12409452). This depletes the pool of uridine-derived pyrimidines and leaves no pyrimidines left to copy the non-damaged, wild-type mtDNA copies.

That's the idea, at least, as far as I understand it, but I think the other research, showing that uridine, in animals without existing heteroplasmy, protects against mitochondrial insults may be relevant to understanding the inconsistent effects of uridine in treating heteroplasmy. I also don't understand, incidentally, why the assumption would be that purines wouldn't be depleted in cells with respiratory chain dysfunction, given that a decrease in ATP levels and the adenylate charge will more or less always, in and of itself, lead to purine depletion from most cells. But in that research on neuroprotection, uridine is neuroprotective partly by its conversion into ribose-1-phosphate (and uracil) and probably also by its effect of providing pyrimidines for other processes (increasing cytidine triphosphate levels for phosphatidylcholine biosynthesis, etc.--all of the research on uridine in neuropsychiatric research--the articles I linked to in my last posting--is focused on that mechanism).

The research on heteroplasmy fed into the research in relation to neuropsychiatric symptoms, and there's some research suggesting people with some psychiatric symptoms may have heteroplasmic mitochondrial DNA in cells in some parts of their brains or in a more widespread pattern of cell-type distribution (http://www.ncbi.nlm.nih.gov/pubmed/15533721). That line of research is not convincing to me, and mitochondrial dysfunction per se is not, by any means, evidence of heteroplasmy.