Potential for Inhibition of Ketogenesis as a Result of Vitamin B12 Deficiency/Depletion: Role of Succinylation of HMG-CoA Synthase & Other Mechanisms

This article [Hegardt, 1999: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1220089)(http://www.ncbi.nlm.nih.gov/pubmed/10051425)] is great and discusses a lot of the mechanisms by which fasting and insulin and other factors regulate ketogenesis. The author discusses the fact that the mitochondrial HMG-CoA synthase (mHMGS) isoform is thought to be rate-limiting for ketogenesis under many different sets of circumstances, and the author discusses the inhibition of mHMGS by its succinylation or mechanism-based (suicide, covalent) inactivation, at an active site cysteine residue, by propionyl-CoA. At first glance, this would seem to suggest that something like cobalamin (vitamin B12, or just B12) depletion would lead to a decrease in the succinylation, thereby, potentially, disinhibiting ketogenesis, but also to an increase in the mechanism-based (noncompetitive) inhibition by propionyl-CoA. Propionyl-CoA accumulates in mitochondria in B12 deficiency [see Brass et al., 1990: (http://jn.nutrition.org/cgi/reprint/120/3/290.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2319347); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22coenzyme+A+metabolism%22+B12)], but B12 deficiency also decreases the formation of succinyl-CoA from methylmalonyl-CoA [due to the decrease in 5'-deoxyadenosylcobalamin-dependent methylmalonyl-CoA mutase (MMM) activity] and, as a consequence, may decrease succinate availability intramitochondrially. But succinate can be maintained from other pathways, and B12 deficiency also may inhibit succinate dehydrogenase activity by causing the accumulation of methylmalonate, derived from an excess of methylmalonyl-CoA [see Toyoshima et al., 1995: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22succinate+dehydrogenase%22+cobalamin)]. That might actually increase succinate accumulation, but it's not really possible to tell what the effect of B12 deficiency would be on the steady-state levels of succinate that would be available for mHMGS succinylation (and, consequently, inhibition). Brass et al. (1990) found that B12 deficiency nonsignificantly reduced fasting beta-hydroxybutyrate levels and that hydroxocobalamin[c-lactam], which selectively inhibits MMM activity, did reduce beta-hydroxybutyrate levels (one of the two major plasma ketones). Propionyl-CoA is known to be increased in B12 deficiency, but some articles have found evidence of mitochondrial proliferation [which is clearly pathological, in this case, as discussed by Krahenbuhl et al., 1990: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22succinate+dehydrogenase%22+cobalamin)], and that type of response could temporarily compensate for the deficits in beta-oxidation and ketogenesis that one would expect to see in chronic B12 depletion. There's an article in the journal Annual Review of Nutrition (I don't have time to cite it, but the article is in the one-issue-per-year, 1992 issue), and the authors try to discount the role of decreases in MMM activity in the neuropathy or subacute combined degeneration of B12 depletion. But the reasoning they use is not valid, in general, largely because of the profound and complex changes in mitochondrial functioning that can result from methlmalonic acid and methylcitric acid, etc. (organic acids that accumulate in B12 deficiency). Most people are not aware that B12 deficiency can cause liver damage and dysfunction. Joshi et al. (2008) [Joshi et al., 2008: (http://www.japi.org/june_2008/corr-476.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18822634)] found evidence of this, and there are other articles on it. I seriously doubt that that jaundice is only due to the intramedullary hemolysis of reticulocytes or erythroblasts. That doesn't make sense to me. I think it's partly or largely the result of impairments in mitochondrial energy metabolism in hepatocytes and other cells of the liver, due to the inhibitory effects of the accumulated acyl-CoAs and organic acids (derived from excesses of their organic acyl-CoAs) on many different mitochondrial enzymes, including mHMGS. I think B12 depletion could reasonably be expected to inhibit both beta-oxidation (there's a great deal of evidence that this is the case) and also ketogenesis (and ketone utilization in neurons, etc.). But that's just my opinion. That first search I linked to (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22coenzyme+A+metabolism%22+B12) looks like it has some articles with some more in-depth data on B12-depletion-induced changes in beta-oxidation or lipogenesis and ketogenesis, and I'll try to look through those at some point. I've discussed the inhibitory effects of organic acids and acyl-CoAs (those that accumulate as a result of B12 depletion) on mitochondrial functioning in general and on TCA cycle enzymes in particular, including succinate dehydrogenase, in many past postings. An impairment in beta-oxidation obviously implies that there will be a deficit in ketone formation, but some of these more specific mechanisms in the regulation of ketogenic enzymes, such as mHMGS, may also become significant in the context of B12 deficiency and other pathological states. I suppose I don't need to say that, in my opinion, cyanocobalamin (one form of vitamin B12) is very inferior to methylcobalamin (another form of vitamin B12). The main reason, as I've discussed in many past postings, is simply that methylcobalamin is *not cyanocobalamin* and does not yield cyanide and is transported much more efficiently than cyanocobalamin is, etc. These are my opinions based on the literature, and there's a vast amount of literature comparing the two forms.