Manganese Toxicity Is a CoQ10 Deficiency

Excess manganese causes mitochondrial dysfunction by inhibiting CoQ10 synthesis.

A 2022 paper in Nature Communications showed that, in yeast and fruit flies, and thus in a mechanism conserved among species ranging from yeast to animals, the singular mechanism of manganese toxicity is that it inhibits the synthesis of CoQ10.

Remarkably, Nature Communications has an impact factor of 16.6, which is considered a “remarkable” level of influence, yet this paper has only been cited eight times.

None of them are original followup research, so this finding has neither been replicated nor refuted, but it is genuinely game-changing.

They found that manganese highly selectively displaces iron in the CoQ7 enzyme, making it dysfunctional. This prevents CoQ10 synthesis, which causes oxidative stress and prevents ATP from being made. Most of the effects can be rescued by CoQ10.

First they disrupted the gene for the ATP-dependent manganese exporter to make manganese accumulate to toxic levels in yeast. Their ability to engage in glycolysis remained normal, but once deprived of glucose to make them rely on mitochondrial respiration, they died.

Bathing normal yeast in excess manganese had the same results.

Then they genetically modified the yeast to genetically overexpress every single gene in their genome and discovered that, apart from the gene they had disrupted in manganese transport, the only other gene that could restore mitochondrial function was the gene for CoQ7.

So, they tested the quinone levels in the manganese-toxic yeast, and they all had very low levels of CoQ6 (the yeast version of CoQ10), and very high levels of the direct precursor that feeds through the CoQ7 enzyme, de-methoxy-CoQ.

Overexpressing CoQ7 in manganese-toxic yeast cells fully restored CoQ6 levels, mitochondrial function, and survival, to normal.

No other enzyme involved in CoQ synthesis was affected.

The expression and transport of CoQ7 itself was not affected. Rather, iron is supposed to be inserted into CoQ7 as it is folded, and iron deficiency, as shown in other studies, will cause CoQ7 to misfold and be degraded. In this study, it was shown that during manganese toxicity, manganese inserted itself into the CoQ7 enzyme during folding. The protein misfolded, and was degraded, just like in iron deficiency.

Providing a CoQ10 precursor that bypassed the CoQ7 step fully rescued the toxicity.

Then they sought to discover whether this mechanisms of manganese toxicity is conserved in animals, so they tested it in fruit flies.

They engineered the fruit flies to lack the exporter of manganese just like the yeast, but only in their muscle cells. They developed mitochondrial dysfunction, low levels of CoQ9 (the fruit fly version of CoQ10), developmental delay, and premature death. Dietary supplementation of CoQ9 or a CoQ7-bypassing precursor fully restored developmental milestones.

However, they did not report the effect of CoQ9 on mortality, and only reported the effect of the CoQ7-bypassing precursor. This only partly rescued the mortality.

It may be the case that this is the exclusive mechanisms of manganese toxicity in yeast, but is only one of the major mechanisms in animals. Or, it may be that dietary supplementation with the CoQ7-bypassing precursor can’t fully restore the CoQ10 levels in the membranes where it is needed.

Among the eight papers that cite this one is a recently updated opinion on the safe upper limit of manganese consumption by the European Food Safety Authority. It says disrupting coenzyme Q10 synthesis is “a possible further molecular mechanism” of toxicity. The main mechanisms, this report says, are as follows:

When in excess, manganese has been reported to disrupt mitochondrial ATP production and induce oxidative stress (Gunter et al., 2012; Malecki, 2001; Zheng et al., 1998). Other proposed mechanisms include direct neuronal toxicity by the inhibition of mitochondrial respiration, leading to energy failure, impaired functions of glial cells (astrocytes and microglia), oxidative stress and excitotoxicity (Morcillo et al., 2021; Nyarko-Danquah et al., 2020).

It isn’t “[another] proposed mechanism” that manganese inhibits mitochondrial respiration when the first mechanism is inhibiting ATP production and inducing oxidative stress. It isn’t “a possible further molecular mechanism” that manganese inhibits CoQ7.

Rather, these can all easily be synthesized into a mechanism where manganese inhibits CoQ7, CoQ10 levels fall, antioxidant defense fails, mitochondrial respiration fails, and ATP production stops, all because CoQ10 levels dropped.

I think it is too early to say whether this is the exclusive mechanism in humans and other animals, but the evidence it is exclusive in yeast appears strong from this paper.

The evidence that it is a major mechanism in fruit flies seems strong.

This needs to be investigated in other animals and humans, but for the time being I think it makes sense to include it as the central theme of a working model for how manganese toxicity works.

CoQ10 does not always solve a CoQ10 synthesis problem, but it often does, and it is often powerful. CoQ10 blood levels are not reliable ways to rule in or out deficiencies in muscle and nervous tissue. If you have reason to know that manganese toxicity is the culprit, removing manganese and making sure iron levels are adequate should be the top priorities. CoQ10 supplementation seems worth trying, after those top priorities have been put in place.

My guide to managing CoQ10 status can be found at Does CoQ10 Deserve a Spot on Your Longevity Plan? I have updated that article to reflect the information on manganese and iron overload genes.

Get my guide to detoxing manganese here: