Vitamin B12 and effects on mitochondria

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis.Singhal NK, Li S, Arning E, Alkhayer K, Clements R, Sarcyk Z, Dassanayake RS, Brasch NE, Freeman EJ, Bottiglieri T, McDonough J.J Neurosci. 2015 Nov 11;35(45):15170-86. 

Mitochondrial changes, including decreased expression of electron transport chain subunit genes and impaired energetic, have been reported inmultiple sclerosis (MS), but the mechanisms involved in these changes are not clear. To determine whether epigenetic mechanisms are involved, we measured the concentrations of methionine metabolites by liquid chromatography tandem mass spectrometry, histone H3 methylation patterns, and markers of mitochondrial respiration in gray matter from postmortem MS and control cortical samples. We found decreases in respiratory markers as well as decreased concentrations of the methionine metabolites S-adenosylmethionine, betaine, and cystathionine in MS gray matter. We also found expression of the enzyme betaine homocysteine methyltransferase in cortical neurons. This enzyme catalyzes the remethylation of homocysteine to methionine, with betaine as the methyl donor, and has previously been thought to be restricted to liver and kidney in the adult human. Decreases in the concentration of the methyl donor betaine were correlated with decreases in histone H3 trimethylation (H3K4me3) in NeuN+ neuronal nuclei in MS cortex compared with controls. Mechanistic studies demonstrated that H3K4me3 levels and mitochondrial respiration were reduced in SH-SY5Y cells after exposure to the nitric oxide donor sodium nitroprusside, and betaine was able to rescue H3K4me3 levels and respiratory capacity in these cells. Chromatin immunoprecipitation experiments showed that betaine regulates metabolic genes in human SH-SY5Y neuroblastoma cells. These data suggest that changes to methionine metabolism may be mechanistically linked to changes in neuronal energetics in MS cortex.
SIGNIFICANCE STATEMENT: For decades, it has been observed that vitamin B12 deficiency and multiple sclerosis (MS) share certain pathological changes, including conduction disturbances. In the present study, we have found that vitamin B12-dependent methionine metabolism is dysregulated in the MS brain. We found that concentrations of the methyl donor betaine are decreased in MS cortex and are correlated with reduced levels of the histone H3 methyl mark H3K4me3 in neurons. Cell culture and chromatin immunoprecipitation-seq data suggest that these changes may lead to defects in mitochondria and impact neuronal energetics. These data have uncovered a novel pathway linking methionine metabolism with mitochondrial respiration and have important implications for understanding mechanisms involved in neurodegeneration in MS.

So with the signficiance statement we don’t need to say anything much as you get the interpretation from the author’s mouths 

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  • Dear MD
    The significance statement might make sense to you, but a plain English version would be handy for those of us who are not scientists……..

    While on the subject of Vit B12 – there are many PwMS who are quite adamant that B12 supplementation does make them feel better – especially in relation to fatigue. At least B12 is non-toxic and if you take "too much" of it, you just piddle it out of your system.

    And the following article provides quite a bit of food for thought on B12 and MS – I found it most interesting that apparently IFN-B-1A has negative impacts on B12 levels for PwMS. The article also raises some interesting points about MS and B12 levels similar to the "reverse causation" issues around MS and Vit D3.

  • I was reading about B vitamins, including B12 and they may interfere with melatonin production at night so it was suggested that they are taken early in the day and not near bedtime.
    I thought that was interesting in connection with the previous posts about melatonin and MS.

  • Is it a coincidence that my MS fatigue seemed to reduce dramatically after I started taking a high potency vitamin B supplement containing 10,000 times the NRV for B12? I'm not swearing by anything though – just another anecdote.

  • How much per day would be advised (to avoid sur-vitaminose?) ? Do you have a specific recommendation? I agree that the significance statement would deserve to be re-written in plain English.

  • Part of the problem with B12 is that the bottom end of the reference range used to decide if you are "deficient" or not varies significantly in different countries. For example, in Japan and some European countries 400nmol/L is the bottom end of the range, whereas in Australia it is 200 nmol/L. Part of the issue that I see is that some countries are still using reference ranges where the level used to decide on deficiency is based on ancient studies where the low end of the range is that necessary to prevent blatant disease states, rather than that which is optimal for good health. Another aspect is that what is OK for one person at the low end of the range can actually be a deficiency for another. Like MS drugs – one size does not fit all.

    I took 1,000 mcg a day for some weeks and my levels came up to around 560 nmol/L and I did feel a lot better. However, it is important to also look at levels of Active B12 as serum B12 can be quite high but Active b12 insufficient. As with all of these things, they need to be in balance, and Active B12 levels should be around 20% of the serum B12 levels.

  • Ooops – an Anon here – I just hit "publish" on comment about B12 reference ranges and the typing gremlins had a go and I've written nmol/L when I meant pmol/L

  • Last time I had a vitamin B12 injection, I ended up paralysed down one side within two hours. It scares the hell out of me.

    • It is the injection of vitamin B12 is quite painful … But if the form of Vit B12 actually absorbed by the body is Methylcobalamin, right or not ?!

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