Vitamin B12, Succinyl-CoA Ligases, and Nucleoside Diphosphate Kinases

This article [Elpeleg et al., 2005: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1196446) (http://www.ncbi.nlm.nih.gov/pubmed/15877282)] is interesting and helps to shed light on the association, discussed in these recent articles by Morath et al. (2008) [Morath et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/17846917)] and Fowler et al. (2008) [Fowler et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18563633)], of methylmalonic aciduria and decreases in succinyl-CoA ligase activity being associated with mtDNA depletion. Succinyl-CoA ligase activity is coupled to the activities of nucleoside diphosphate kinase enzymes, and Elpeleg et al. (2005) found evidence that succinyl-CoA ligase activity is required for normal mtDNA formation (i.e. replication and turnover). Given that genetic disorders that reduce the activities of succinyl-CoA ligases (different subunits of succinyl-CoA ligase whose reduced activities can be partially, but not adequately, compensated for by the activities of other isoforms or subunits) produce methylmalonic aciduria, it's conceivable that vitamin B12 (cobalamin) deficiency could produce mtDNA depletion by indirectly inhibiting the activity of succinyl-CoA ligase. It's sort of implied in those articles, and it's interesting to think about.

Elpeleg et al. (2005) are just suggesting that reductions in succinyl-CoA ligase activity produce mtDNA depletion by, in all likelihood, deranging the salvage of purine nucleotides and thereby reducing their availability for mtDNA synthesis (via their conversion into dNTP's, etc.). I think there's something with the directionality and reversibility of the succinyl-CoA ligase enzymes' activities, when a decrease in methylmalonyl-CoA mutase (MMM) activity, as in cobalamin deficiency or genetic disorders, reduces succinyl-CoA availability. Yeah...here's an article that discusses the fact that succinyl-CoA ligases are reversible and normally do catalyze the reverse reaction, to supply succinyl-CoA for heme biosynthesis and, apparently, ketone formation [Ostergaard et al., 2007: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1950792) (http://www.ncbi.nlm.nih.gov/pubmed/17668387)]. That's interesting, and I'd be willing to bet that the directionality or level of activity of succinyl-CoA ligase is disturbed in cobalamin depletion and disrupts nucleotide salvage or mtDNA synthesis, to some extent, maybe by leading to increased activities of the reverse reactions of the succinyl-CoA ligases (to compensate for the reductions in succinyl-CoA formation that occur in response to cobalamin depletion) and the nucleoside diphosphate kinases whose activities are coupled to the activities of the succinyl-CoA ligases. This article [Wajner and Coelho, 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9427143)] gets at that concept, and the authors note that propionyl-CoA, which accumulates in cobalamin deficiency and genetic MMM deficiency, inhibits succinyl-CoA ligase. Methylmalonic acid also inhibits succinate dehydrogenase activity, and that would be expected to further derange the nucleoside diphosphate kinase activity (probably more by just inhibiting the overall TCA cycle, in that case) (Wajner and Coelho, 1997).