References in Relation to CoQ10 and Uridine in Mitochondrial Disorders

These are some of the articles that discuss the rationale for using uridine to treat mitochondrial dysfunction. It's not just that inhibition of mitochondrial function inhibits de novo pyrimidine biosynthesis (uridine biosynthesis). This article shows the way a genetic disorder (creating a reduction in the activity of para-hydroxybenzoate polyprenyltransferase) that impairs CoQ10 biosynthesis, in a human, can reduce complex I and II activities (transferring electrons, via CoQ10-dependent enzymes, to complex III) and thereby reduce cell growth. This article also shows that cell growth in fibroblasts from a human with the mutation can be restored with either exogenous uridine or coenzyme Q10. This type of research shows that a reduction in the activity of complex II and the dihydroorotate dehydrogenase activity that is coupled to complex II not only reduces de novo uridine biosynthesis but reduces overall cell growth in a uridine-reversible manner:

http://www.ncbi.nlm.nih.gov/pubmed/17374725 (Jose Lopez-Martin et al., 2007)

This article shows that inhibition of the activity of complex I and of the respiratory chain, overall, inhibits nucleotide biosynthesis and causes a drastic depletion of pyrimidine (uridine + uridine-derived pyrimidines) nucleotides. The article also shows that purine metabolism is disturbed by mitochondrial dysfunction. The overall purine pool was more or less preserved, but the adenylate/guanylate charges were decreased (more purine nucleotide monophosphates and diphosphates in relation to triphosphates):

http://www.ncbi.nlm.nih.gov/pubmed/15571245 (Gattermann et al., 2004)

This article shows that inhibition of complex IV (cytochrome c oxidase) activity with the azide anion does not cause pyrimidine depletion, given that dihydroorotate dehydrogenase is coupled to complex II. The simplistic explanation for this is that complex IV is the terminal enzyme complex of the electron transport chain and is downstream of complex II and complex III. In spite of the fact that complex IV inhibition did not produce pyrimidine nucleotide depletion, complex IV inhibition did produce neurological damage that could be partially prevented with uridine pretreatment (from triacetyluridine or PN401, a.k.a. RG2133, a uridine prodrug). The authors of the article also discuss the fact that complex II inhibition, in animals lacking any genetic disorder affecting complex II activity, does produce pyrimidine depletion and neurological damage that can be partially prevented by pretreating the animals with exogenous uridine:

http://www.ncbi.nlm.nih.gov/pubmed/16330000 (Garcia et al., 2005)

I'll put up other articles, at another time, that discuss the way complex III activity is required to maintain dihydroorotate dehydrogenase activity, but the original idea was that reductions in both complex III and IV activities would compromise pyrimidine biosynthesis (Loffler et al., 1997: http://www.ncbi.nlm.nih.gov/pubmed/9309676). In view of that article by Garcia et al. (2005), this may not be the case. But that's just one article. It's interesting, though. The detailed picture of this is much more complicated and isn't well understood (the ways in which changes in the individual subunits of complex II, for example, affect the activities of dihydroorotate dehydrogenase or other mitochondrial enzymes). Here's one article that discusses the potential necessity of complex III activity for the maintenance of dihydroorotate dehydrogenase activity. The authors hypothesize that complex III can maintain complex II activity by oxidizing the reduced CoQ10 (CoQH2) that's been produced by complex II activity (I keep getting the article fragment, but here's the link):

http://www.fasebj.org/cgi/content/abstract/03-0520fjev1 (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/15180963?dopt=Abstract) (Dimitry Spitkovsky et al., 2004)