What can cause manganese to be used up?

[renski]

Hello,

My manganese levels in blood went down, I tested manganese and a whole bunch of other stuff before starting any supplements but I started taking a number of things around the same time so I can't possibly know which one has caused it.

This is what I've been taking:
Tri-fortify glutathione
B1 (Benfotamine)
P5P
B2 and R5P
B3 (Niacitol and Niacinamide)
Biotin
Hydroxy/Adenosyl B12
Lithium drops
Zinc
Mineral complex (which has manganese) about twice per week

Thanks

 

[aaron_c]

Andrew Cutler mentions iron, phosphorus, and calcium as interfering with manganese absorption.

 

[CCC]

It could be B2. One of the megaB2 threads had more about it ('B2 i love you' or 'B2 not so great' (not sure about that second thread title).

If that is the case, it means your body has started working again. From what I can remember, it's not so much an issue of B2 sucking out all the manganese, but just that the things B2 does need manganese. So you've used it up (so to speak).

 

[Learner1]

Superoxide dismutase (SOD). which neutralizes superoxide made by mitochondria during energy production uses it. Manganese deficiency reduces SOD production, which may result in damaged mitochondrial membranes.

In addition to supplementing a little manganese, ensure you have enough folate and B12, to promote BH4 recycling which will help membranes.

If this has been going on for a while, you might also look into NT Factor to replenish lipids in membranes to repair them, as leaky mitochondrial membranes lessen ATP production.

 

[renski]

Alright thanks everyone.. I've started to add a little Folate the last few days. I've been thinking about phospholipids too, the Tri-fortify is liposomal so it has some phosphatidylcholine.

@Learner1: When you say NT factor, do you just mean phospholipids or the product that has much more (carnitine, CoQ10 etc)? It's been going on for about 8 years but symptoms have been chronic for past 2 years since upsetting the gut.

 

[Learner1]

@Learner1: When you say NT factor, do you just mean phospholipids or the product that has much more (carnitine, CoQ10 etc)? It's been going on for about 8 years but symptoms have been chronic for past 2 years since upsetting the gut.

I take Allergy Research NT Factor as its the only version without corn. Its licensed to 2 or 3 manufacturers, I believe.

I take Thorne Q Best separately, which allows me to change the dose, if needed.

And I take injectible carnitine. There is some concern that with the wrong gut bacteria, they can make too much of something called TMAO that's bad for your heart. My doctor tested me, found I had too much of it, so I won't return to it orally til my gut is ready to behave with it.

 

[renski]

@CCC @Learner1 and everyone:

Any ideas what would cause manganese to be low? Gut issues, what about high ammonia? Oxalates seem to deplete manganese as well? are certain B vitamins needed to absorb manganese?

 

[Learner1]

My experience has been that its used to make MnSOD used to defend superoxide radicals that mitochondria make as a byproduct every time they make an ATP molecule. I had a mito function test showing 2 complexes functioning at 370% of normal, throwing off huge amounts of free radicals.

If you can't make enough MnSOD, then peroxynitrites will instantaneously get made when the superoxide radicals come into contact with NO. This will damage mito membranes and impair complex I. The 2 attached documents show how to reverse the peroxynitrite problem. Ensuring you have adequate MN fir the MnSOD is important. Another clue is depleted glutathione and other antioxidants.

Oxalates definitely can be a factor, especially if your microbiome has been compromised by antibiotics killing off oxalobacter. Ingesting Roundup treated foods doesn't help. And many foods like wheat, whole grains, spinach, nuts, raspberries, tea and chocolate are high in oxalates building up over time. Vitamin C can convert to oxalates. If you are deficient in B6, which is needed to help get eid of them, that's a problem. Pain, smelling like sulfur, reduced kidney function and mitochondrial damage are symptoms. Solutions involve improving the microbiome, gall bladder function, and taking digestive enzymes and calcium citrate with meals.

There are likely other areas to look into, too, byt as these two scenarios are highly lijely for ME/CFS patients, they're worth investigating.

 

[renski]

It's confusing because there are oxalates in diet, but the oxalates also build up in the cells with the heavy metals (https://mthfrsupport.com/2018/03/understanding-sulfation-and-oxalate/), so it seems detoxing the metals is the fix, even though the B vitamin deficiencies supposedly are related to oxalates as well.

Can you detox without methylation? Just using Vitamin C, NAC etc?

Heavy metals and things like high free copper and manganese deficiency in the cells.
Oxalate love grabbing metals and minerals. So when you have an oxalate overload you will often see heavy metals toxicity, high free copper and manganese deficiency just to name a few.
Andy Cutler was right but he was also wrong. He stated that you detox metals by the use of ALA (alpha lipoic acid) which is right. ALA is a cofactor on the glyoxylate metabolic process. Imagine oxalate as kitchen magnets. They are chelators of metals and minerals. So this oxalate sitting in damaged tissues and organs collect heavy metals you would normally dump. ALA is one of the components of this process that removes the oxalate and by removing the oxalate it in turn removes metals. And it also removes minerals like high free copper that do not make it to the cell wall because of the oxalate overload. So this is where he was wrong. It is actually removing the oxalate that have the heavy metals and minerals like high free copper bonded to the oxalate.

 

[Learner1]

It's confusing because there are oxalates in diet,

Many people are fine with oxalates, especially if they have happy oxalobacter, lactobacillus, and bifidobacteria. And if they eat dairy with calcium with high oxalate foods. But throw in a genetic tendency, antibiotics, and/or a dairy allergy or vegan diet, and/or a little Roundup, and you have a recipe for trouble.

but the oxalates also build up in the cells with the heavy metals (https://mthfrsupport.com/2018/03/understanding-sulfation-and-oxalate/), so it seems detoxing the metals is the fix, even though the B vitamin deficiencies supposedly are related to oxalates as well.

Can you detox without methylation? Just using Vitamin C, NAC etc?

Yes, heavy metals will build up.

A key to detoxing is using the appropriate method for the appropriate toxin. Oxalates don't get detoxed like a heavy metal. They need to be bound by calcium and taken out of the body in feces and urine. If you have such a problem, improving digestion, with probiotics, digestive enzymes, gall bladder support and I-glutamine for gut lining is needed. Then taming calcium or potassium citrate or lemon water before and with meals. And being on a low oxalate diet. Also, unfortunately, vitamin C over 4g convetts to oxalate.

Minerals combine with oxalates to make a soap, and so one ends up depleted of various minerals, so checking the status of other minerals might be wise.

You need to get rid of the metals by chelating them, while supporting detox pathways.As stated above, ALA can get depleted, along with other antioxidants and B vitamins and magnesium, so paying attention to these would be important. And NAC, of course.

Can you probide the source for your quote, please?

 

[renski]

That quote was from the mthfrsupport URL.. they talk about how oxalates take up the place of sulfur. I'm not really talking about oxalates from the diet, more the endogenous oxalates

It's interesting because some doctors I've seen don't use chelation to get the metals out, they just use B complex/minerals, B3 in particular for glutathione, but that just makes me worse. And then you have people like Dr. Shade, which just uses glutathione and ALA to detox..

 

[renski]

You need to get rid of the metals by chelating them, while supporting detox pathways.As stated above, ALA can get depleted, along with other antioxidants and B vitamins and magnesium, so paying attention to these would be important. And NAC, of course.

Is there an order to it, if deficient in ALA, phospholipids, B vitamins, Vitamin E/C, etc?

 

[percyval577]

My experience has been that its used to make MnSOD used to defend superoxide radicals that mitochondria make as a byproduct every time they make an ATP molecule. I had a mito function test showing 2 complexes functioning at 370% of normal, throwing off huge amounts of free radicals.

If you can't make enough MnSOD, then peroxynitrites will instantaneously get made when the superoxide radicals come into contact with NO. This will damage mito membranes and impair complex I.

(We had this discussion already)

It´s my understanding that MnSOD will catalyze the superoxide ions to become H2O2. It cannot be said that the one or the other is bad or good, it depends on their amount and on the amount of other components. I have read that MnSOD is very thightly regulated and difficult to influence, though EBV and borrelia have been shown to cause autoantibodies against MnSOD, suggesting that there is too much MnSOD (probabaly due to high concentration of Mn or inhibiting the Mn exporter ZnT10, resp.). In contrast, coxilla burnetti does not contain any Mn, and can survive in the phagosomes.

Logically - which doesn´t say too much -, if there is slightly too much MnSOD the superoxide ions (together with NO) will not slow down complex I with all its artificial looking iron-sulfur-centers, and too much energy might be produced, in a first step. Then cf. Bouabid et al 2016 (on neurotoxic levels) p. 686:

As mentioned previously, Mn accumulates in mitochondria using the calcium uniporter, and this accumulation leads to a disruption of calcium homeostasis (Gavin et al. 1999), inhibiting energy production particularly by reducing the complex‐1 activity in the electron transport chain and subsequently leading to the formation of reactive oxygen species (Zhang et al. 2004).

On the other hand, concomittantly with the lesser amount of superoxide, there may be too many other "signaling metabolite" ROS generated from the H2O2 (which needed to be also regulated by scavanging catalase or GPX). It seems that Mn works specifically at complex II to actively let pass H2O2 into the cytosol: Manganese ions enhance mitochondrial H2O2 emission from Krebs cycle oxidoreductase by inducing permeability transition (Bonk et al 2016). A mitochondrial transition pore for ROS has been tried to implicate in aging (elevated and prolonged transition).

Generel, when there is much too much superoxide (and NO), mitochondria may burst [correction: may leak] and finally may induce apoptosis.


For metabolic diseases Longman and Yang´s review suggests an U-shaped relationship with Mn intake.

[For the complexity] Nalkiran et al 2015, in the Journal "Anticancer Research"

The result of our study showed that GPX1 gene expression was statistically significantly different (two-fold lower than normal tissue; p<0.05) between normal and tumor tissue.

In contrast with these results, some studies showed increased GPX activity in the tumor tissue (e.g. breast cancer) compared with normal cells (42, 43). Oberley et al. examined the relationship between MnSOD and GPX and established that the overexpression of CuZnSOD and MnSOD genes inhibited the growth of human glioma cells; however, they suggest that the effect could depend on the intracellular GPX activity (33).

On the contrary, there are some studies that reported overexpression of SOD and GPX together, which led to the rapid growth of tumor cells (44, 45). The findings of our study showed that there was no statistically significant difference between the gene expression profile of GPX1 and histopathologic data when we examined parameters such as the presence of distant metastases, perineural invasion, tumor grade, and the presence of differentiation.

Unfortunately, we observed no meaningful relationship between expressions of both genes and serum levels.

@renski , generally speaking, low serum Mn could also be a compensation, couldn´t it? For some experiences with Mn supplementation see here: threads/low-manganese-diet-further-serious-effect-of-mn-has-been-confirmed.58833/page-2#post-974705. One more member has reported a good effect, and nanonug has reported at least no bad effects.

 

[percyval577]

It might be worth to add from the cancer article (@Learner1):

Some studies showed that MnSOD activity is low in several tumor types; however, the fact that there is considerably higher activity of MnSOD in cells of colon, lung, stomach and esophageal cancer compared to normal tissues has been confirmed by a number of other research groups (1, 32-38).

In contrast: "Increased [MnSOD] expression surpresses the malignant phenotype of human meloma cells", Church et al 1993

Also worth might be to reiterate the Bouabid quote with Harischandra et al 2019 (on neurottoxixity)

Mn also shares the Ca2+ uniporter mechanism and the rapid mode (RaM) of Ca2+ uptake of mitochondrial calcium influx, resulting in Mn sequestration in mitochondria, which gets removed only very slowly from the brain (Gavin et al., 1999). This Mn accumulation inhibits the efflux of calcium, decreases MAO activity, and inhibits the respiratory chain and ATP production (Zhang et al., 2003)...

Underline edited.

 

[Learner1]

It´s my understanding that MnSOD will catalyze the superoxide ions to become H2O2.

If it's adequate, yes. If it's not adequate, likecun a case where Mn is insufficient, superoxide will react with NO to make ONOO-, peroxynitrite. You can read the paper I attached above or the one attached here.

Logically - which doesn´t say too much -, if there is slightly too much MnSOD the superoxide ions (together with NO) will not slow down complex I

We were discussing when there is NOT enough MnSOD, such as when one is deficient in Mn. The attached paper discusses inhibition of complex I by peroxynitrites.

I might also add, oxidative and nitrosative stress is a known feature of ME/CFS, as in the attached paper, but also, at the 4/19 NIH conference, in his summary, Ron Tompkins specifically mentioned this as a known feature, even though none of the presentations discussed it. The Pall and Nicolson papers discuss it.

And, MitoSwab, who did my mitochondrial functiin testing, told me that the pattern with the ME/CFS patients they've tested is complex I inhibition.

My labs, which showed high nitrotyrosine, a marker for peroxynitrites, high NO, depleted antioxidants and manganese, low complex I function, and overactive complexes II and IV, spell out this pattern found in other patornts well, and I've responded well to treatment to minimize peroxynitrites and repair the damage with the nutrients Pall and Nicolson suggest, along woth supplementing a small amount of manganese. My energy improved quite a lot as well, so this is more thsn probing a theory in paper.

. It seems that Mn works specifically at complex II to actively let pass H2O2 into the cytosol:

And, in a case of ooveractivity of complex II, as I had, one would use up Mn faster and become depleted.

Then, if one was depleted in MnSOD, there would not be enough to defend superoxide radicals and they would become peroxynitrites, not H2O2.

The findings of our study showed that there was no statistically significant difference between the gene expression profile of GPX1 and histopathologic data when we examined parameters such as the presence of distant metastases, perineural invasion, tumor grade, and the presence of differentiation.

This is a paper about cancer. In all cancers, mitochondria are abnormal, in shape, features and/or function. This does not translate to ME/CFS patients, unless they also have cancer.

Generel, when there is much too much superoxide (and NO), mitochondrias may burst and finally may induce apoptosis.

Having read extensively on this topic and listening to all the doctor/scientific presentation at 2 mitochondria conferences, I have not come across exploding mitochondria resulting from overactivity or ones making peroxynitrites. They do, however, recycle every 6-8 weeks or so, so if one has misbehaving mitochondria, as ling as they're less than about half the total, it is possible, by feeding the nutrients they need, to encourage happier ones to form, which is what Nicolson is doing and what I've had good luck in experimenting with.

 

[Learner1]

It might be worth to add from the cancer article (@Learner1):


Also worth might be to reiterate the Bouabid quote with Harischandra et al 2019 (on neurottoxixity)

Again, cancer does not equal ME/CFS. You cannot compare what mitochindria are doing.

Obviously you do not want too much Mn. More is not better. Too much of anything is toxic, and metals are worth being respectful of. I suoplemented a small amount of Mn for a few months and retested. I was sufficient, but now, several months later, it's going down again, this time, I believe, due to the oxalate problem which I'm currently working on.

 

[percyval577]

If i -t's adequate, yes. If it's not adequate, likecun a case where Mn is insufficient, superoxide will react with NO to make ONOO-, peroxynitrite.

And the ONOO will react with the iron sulfur centers, which are sweet in a row sitting there, for "some reason" (I would say, for slowing down the complex I, a regulation).

We were discussing when there is NOT enough MnSOD, such as when one is deficient in Mn. The attached paper discusses inhibition of complex I by peroxynitrites.

I wouldn´t be astonished to be low, though I am sensitive to it.

I might also add, oxidative and nitrosative stress is a known feature of ME/CFS, as in the attached paper, but also, at the 4/19 NIH conference, in his summary, Ron Tompkins specifically mentioned this as a known feature, even though none of the presentations discussed it. The Pall and Nicolson papers discuss it.

This is a known guess, but the interpretation as well as a confirmation are uncertain.

And, MitoSwab, who did my mitochondrial functiin testing, told me that the pattern with the ME/CFS patients they've tested is complex I inhibition.

I would well like to agree, though as a result of a second step under high Mn. THough the MnSOD might not be the main thing, I guess.

My labs, which showed high nitrotyrosine, a marker for peroxynitrites, high NO, depleted antioxidants and manganese, low complex I function, and overactive complexes II and IV, spell out this pattern found in other patornts well, and I've responded well to treatment to minimize peroxynitrites and repair the damage with the nutrients Pall and Nicolson suggest, along woth supplementing a small amount of manganese. My energy improved quite a lot as well, so this is more thsn probing a theory in paper.

I would also expect to be found with nitrotyrosine. That NO significantly depletes Mn were new to me. I gave above other experiences with Mn here on the forum. I shall well had a double impact, EBV with MnSOD autoantibodies, and borrelia, same.

And, in a case of ooveractivity of complex II, as I had, one would use up Mn faster and become depleted.

Then, if one was depleted in MnSOD, there would not be enough to defend superoxide radicals and they would become peroxynitrites, not H2O2.

MnSOD regulates them both, one relative to the other. The question is, how much superoxide (slowing down complex I) and how much H2O2 (being converted into all the other ROS).

 

[renski]

Completely derailed this thread, thanks

 

[Learner1]

@percyval two points:

1) you can test with the tests I did to find out.
2) here is the abstract of article I attached above - maybe if you read it, you'll have a better understanding of how it works.

 

[percyval577]

@Learner1 The article is from 2004, and it tries to provide a focus. It says e.g. on p 45 that some nitric oxide+ groups (so hardly in ONOO-) are quite freely interchangable between S-nitrosothiols, but there is no reasoning already why this could be an important chance for an organism. What can it do by this chemical property? The article though seems to know about this limitation very well.
The article says also: ONOO "... which can oxidise or nitrate other molecules, or can decay producing other damaging species (possibly the hydroxyl radical ´OH and NO2)", now OH- is derived from H2O2 (though I admit I don´t know how important this in the matrix may be).

Then I need to correct myself: superoxide is produced in complex I mainly when the chain runs in reverse direction, same seems to be the case with complex III. (In complex I O2 reacts presumably with the FMN side.)
So I would need to say that superoxide (O2-)with NO slows down the reverse chain (if this made any sense), but thereby also inhibiting - irreversible until new units are assembled - the normal chain.
Then the question is: why would this be, and under which circumstances can this be pathological. I gave the neurotoxical finding where high Mn causes complex I shut down, by which mechanism ever, and may this already be pre-toxical on its way or not.


In plants then a Mn starvation leads to reduced growths, but the MnSOD stays stable: "...MnSOD activity ... remained unchanged in the nramp2 mutant, regardless of the Mn regime." and "Interestingly, MnSOD activity in wildtype plants was uneffected by Mn starvation." page377-378, Alejandro et al 2017: "Intracellular Distribution of Manganese by the Trans-Golgi Network Transporter NRMP2 is critical for photosynthesis and cellular redox homeostasis". NRMP2 then is the same as DMT1, so very conserved.

I wanted to say, that the reodox balance may be that tightly regulated that you may not influence a major technical player (MnSOD) by nutrition. Though I think that a lot of things are influencable indeed by nutrition.
Mn amounts may well influence other enzymes. AND I would be very carefully with this almost outstanding metal.