Methylmalonic Acid, Vitamin B12, and mtDNA Depletion in Renal and Neurological Deterioration

This is an interesting article [Morath et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/17846917)] that discusses the prevalence of kidney problems and renal failure in people with methylmalonic aciduria/acidemia. Methylmalonic acid (MMA) also accumulates in vitamin B12 deficiency, and many people with genetic mutations that cause MMA can be treated with large doses of vitamin B12. Many people with genetic mutations that cause methylmalonic aciduria are not able to completely control their neurological symptoms and kidney-related problems, such as proteinuria and glomerulonephritis. Researchers are not entirely sure why MMA produces such severe phenotypes, but it has a lot to do with mitochondrial dysfunction. The basal ganglia are severely affected in methylmalonic aciduria, especially neurons in the globus pallidus.

The brain and kidneys are both very sensitive to reductions in blood flow, and the kidneys, like the brain, have tremendously high metabolic rates. Researchers have fairly recently found that, in the hours after a meal and during fasting (more than 10-12 hours after a meal), the kidneys produce between 15 and 25 percent of the glucose (from gluconeogenesis more than glycogenolysis, given that the kidneys don't store much glycogen) that's released into the blood [Christian Meyer et al., 2002: (http://ajpendo.physiology.org/cgi/content/full/282/2/E419) (http://www.ncbi.nlm.nih.gov/pubmed/11788375?dopt=Abstract)]. This helps explain why people with liver disease tend to have proteinuria and renal dysfunction, given that there would potentially be higher metabolic demands placed on the kidneys under those circumstances. Exercise-induced lactate elevations can produce transient proteinuria, even in healthy people. Parts of the kidneys, such as the proximal tubule epithelial cells, have a high oxidative capacity and can oxidize lactate to produce ATP, but the cells are nonetheless sensitive to metabolic insults. Proteinuria can be produced by ATP depletion per se, and the reabsorption, by active transport into the proximal tubules, of proteins and small molecules, is metabolically very demanding.

The interesting thing in that article is that methylmalonic aciduria is thought to produce mitochondrial DNA depletion over time. Methylmalonic acid and methylcitric acid have been shown to interfere with the functions of many different mitochondrial proteins, but the recent research suggests that those "direct" toxic effects can gradually produce indirect, secondary effects, such as a reduction in the mtDNA copy number. Different cell types in the kidneys and also the brain tend to be vulnerable to mtDNA depletion and can't simply proliferate and, in theory, use the replicative advantage of cells with a higher percentage of wild-type mtDNA to "weed out" the cells with drastic reductions in copy number or high percentages of mutant mtDNA copies.

This is relevant to vitamin B12 deficiency and subacute combined degeneration, and this suggests that the methylcobalamin/folate-mediated increases in thymidylate synthase and methionine synthase activities, producing homocysteine reduction and decreases in uracil misincorporation, may not be the only mechanisms by which vitamin B12 deficiency could produce neurological degeneration. This is already known, that methylmalonic acid contributes to the symptomatology and neurodegeneration in vitamin B12 deficiency. But the association of mtDNA depletion with methylmalonic acid accumulation is rather new. That effect of chronic, MMA accumulation could explain the poor outcomes that many people with subacute combined degeneration have. They tend to get some benefit from vitamin B12 repletion, but they also tend to remain in a fragile state and experience relapses, etc.