"History" of Mitochondrial DNA Depletion-Induced Uridine Auxotrophy in Cultured Cells

This is a good article that discusses some of the history related to uridine auxotrophy, produced by mitochondrial DNA depletion by the DNA polymerase-gamma inhibitor ethidium bromide, in cultured cells (uridine and pyruvate auxotrophy, more specifically, but the authors discuss the fact that exogenous pyruvate causes lactic acidosis and isn't used to treat mitochondrial disorders):

http://www.ncbi.nlm.nih.gov/pubmed/17460185 (Olgun et al., 2007)

It's interesting, though, that aspect about pyruvate, because that sounds like a pretty big issue. It's likely that these high concentrations of uridine, such as from PN401/triacetyluridine, are, in fact, indirectly providing pyruvate, via a ribose-1-phosphate-mediated increase in glycolysis. These cell-culture models of mtDNA depletion aren't perfectly applicable to human aging, but it provides a framework for research. Given that folate deficiency has been shown to produce mtDNA depletion, it's conceivable that something like L-methylfolate, in conjunction with uridine, could help increase the mtDNA content and also limit further increases in the deoxyuridine/deoxythymidine ration in mtDNA.

There's an interesting article that shows the way an increase in the mtDNA content can sometimes lead to PARP activation. But if the reduction in PARP protein content and activity, in response to mtDNA depletion resulting from ethidium bromide, comes at the expense of the mitochondrial membrane potential, it seems like that's a pretty extreme example. But it shows the way a reduction in mtDNA content could be, speaking very subjectively, like a kind of "diminished state" for a cell that would protect against apoptosis via PARP (even though this survival could prevent PARP-mediated DNA repair and, as the article shows, lead to a reduction in the responsiveness of the cells to chemotherapeutic drugs):

http://iospress.metapress.com/content/at174516q463887u/ (Loredana Moro et al., 2008)

But those types of findings might help guide research into the treatment of mitochondrial disorders.