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Mitochondrial Dysfunction – A Biomarker for Fibromyalgia and ME/CFS?

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By Clark Ellis • • June 5, 2013

A recent study from Spain, suggests that mitochondrial dysfunction could be a differentiating marker between fibromyalgia (FM) and chronic fatigue syndrome (CFS), as well as distinguishing both patient groups from healthy controls. This alone could be highly significant but the paper also reports correlation with oxidative stress (where free-radicals damage your cells, and even your DNA), which may highlight potential treatment opportunities.

A Bit About Mitochondria

Each of the cells in your body contains mitochondria. A mitochondrion is shaped like a tiny capsule and exists within the cytoplasm of your cells. They are referred to as ‘organelles’ because they are to a cell, what an organ is to us. Mitochondria fulfill several tasks for our cells, the most important of which is called oxidative phosphorylation, which is a large part of cellular respiration. Cellular respiration is the process of creating energy from nutrients with the help of oxygen. This energy drives all of the functions of all the cells in your body.

Muscle cells that require a lot of energy, contain thousands of mitochondria, whereas other cells which require less energy have fewer. So there is a relationship between the energy requirement of a cell and how much mitochondria it contains.

Mitochondria are unique in the body in that they have their own DNA, separate from the chromosomal DNA you find in the nucleus of each cell. This enables them to reproduce independently of the host cell. Everybody inherits their mitochondria from their mother, and your mother inherited it from her mother, and so on. Genomic sequencing has shown that mitochondria are closely related to the bacteria Rickettsia prowazekii, suggesting an ancient shared origin.

Mitochondrial diseases already exist where the genes encoded by the mitochondrial DNA have mutated. Each mitochondrion contains several copies of its own DNA, which protects it against mutation, but if too many mutations occur then it can cause the mitochondria not to function correctly. It is not hard to see that this would have a potentially dramatic effect on a person’s health, as everything in each cell is driven by the energy produced by mitochondria. It is perhaps of note, that mitochondrial diseases often present as neurological disorders (Zeviani et al. 2004). With FM recently being reported to present like mitochondrial myopathy, you can see why researchers are looking at the DNA in FM and CFS.

However, any mitochondrial dysfunction that may exist in FM or ME/CFS is not necessarily related to mitochondrial genes. It could be as a result of nutrient deficiencies, chemical exposure (Myhill et al. 2012), or as a result of oxidative stress.

In the process of generating energy in the form of ATP, mitochondria also produce volatile oxidative byproducts which have the potential to damage the mitochondria and the cells they inhabit. The body has a system in place to clean up these oxidative products, but if there is dysfunction in the process then you’re in trouble. Dr. Cheney has suggested that this may result in the down-regulation of ATP production as a means of avoiding further oxidative stress. However, oxidative products can come about as the result of another disease process such as increased pro-inflammatory cytokines which have been reported elsewhere in these diseases.

The History of Mitochondria in FM and ME/CFS

Mitochondrial dysfunction has been linked with FM and ME/CFS quite a bit in recent years, but such abnormalities, at least in ME/CFS, were reported as far back as the beginning of the 90s in the UK by the doctors Behan. Since then several doctors have looked closely at mitochondria including Dr. Myhill in the UK, who with colleagues, reported stark mitochondrial dysfunction in CFS patients compared to controls, Dr. Vermeulen in the Netherlands and Dr. Cheney in the US, among others.

A 2010 study of mitochondria in FM reported dysfunction and oxidative stress (Cordero et al.), and a recent study from the same group this year suggested that inflammation could be a mitochondrial dysfunction-dependent event.

Despite the research attention this area has had over the years, some findings have conflicted and so there is more importance than ever to ensure the accuracy of results and to get into the details of the problem when dysfunction is found.

What Exactly is Being Reported?

Dr. Castro and his team have reported on a number of markers related to mitochondrial function and how they differ between patients with FM, ME/CFS and healthy controls. This is a story of one thing leading to another – when one measure appeared low, the researchers examined markers that might explain the low reading, and this resulted in several related abnormalities being uncovered which appear to correlate. Below, we go into detail on each of these markers.

The researchers looked at blood mononuclear cells (PBMC). The obvious advantage of this over a tissue study is that this could more readily translate to a viable test for these diseases.

Levels of CoQ10 and ATP

Co-enzyme Q10 is a powerful antioxidant as well as being one of the essential molecules required by mitochondria in the production of energy. That energy is produced in a biochemical form known as ATP (Adenosine triphosphate). So, with CoQ10 and ATP molecules being lower in both patient groups compared to controls, it might explain some of the symptoms we experience, and is clear evidence of a biological problem in the diseases. This study showed that CoQ10 was about half what it should be in ME/CFS and FM groups. The level of ATP was even worse at about a quarter of what it should be.

Mitochondrial DNA Mass (mtDNA/gDNA ratio)

Although cellular respiration is not the only method your body has to produce ATP it is by far the main producer and so low ATP levels suggest that the mitochondria is affected. Therefore, Dr. Castro and his team looked at the level of mitochondrial DNA in patients compared to controls.

It is important to understand that each cell may contain many mitochondria, and each individual mitochondrion itself contains multiple copies of its own DNA. Therefore, this measure – mtDNA – represents the total mass of mtDNA, compared to gDNA.

gDNA is an abbreviation for genomic DNA (i.e. chromosomal DNA from a cell’s nucleus). The measure used in this study is the ratio of mtDNA compared to gDNA.

In the FM patients, this ratio was found to be low compared to healthy controls, suggesting that there were fewer mitochondria in the cells than there should be. In three FM patients, it was depleted.

In CFS patients the ratio was higher than normal, but not significantly so.

Levels of Lipid Peroxidation Indicative of Oxidative Stress-Induced Damage

Each of our cells has a membrane, composed of lipids, which separates the interior of the cell from the exterior environment. Additionally, each mitochondrion possesses an inner and outer membrane.

Lipid peroxidation is the process by which oxidative products (some of which are created as byproducts of cellular respiration) react with these membranes, resulting in cellular damage.

Dr. Castro and his team have reported higher levels of lipid peroxidation in ME/CFS (almost double normal levels) and much higher levels in FM (almost three times as high as normal). This strongly suggests that our cells (and likely our mitochondria too) are taking damage via oxidative stress.

Citrate Synthase Activity

Citrate synthase (CS) is an important enzyme at the beginning of the Kreb cycle (or citric acid cycle) and although this cycle takes place within the mitochondria, this enzyme is expressed by chromosomal DNA rather than the DNA of mitochondria.

The Kreb cycle produces a small amount of ATP, but more importantly it is a pre-requisite step before mitochondria can perform the most important part of cellular respiration via the electron transport chain (ETC), by preparing the molecules that are required for the ETC. Without CS, cellular respiration would be severely limited. Additionally, it has been demonstrated by Larsen et al. that CS correlates with mitochondrial mass in healthy subjects. So you can see why the researchers looked here.

It is reported here as being on average, less than half the normal level in FM patients, and normal in ME/CFS.

Levels of PGC-1α and TFAM

Having found that the mass of mtDNA in FM was lower than healthy controls and ME/CFS patients, the researchers looked at two proteins involved in the replication and regulation of mtDNA copy numbers within those mitochondria.

These proteins are also involved in protecting mitochondria from oxidative damage – again, you can see why they looked here given the oxidative stress indicated in previous tests. These proteins were found to be significantly lower than normal in FM patients, but insignificantly different in ME/CFS patients, correlating with the results of their other studies.


Dr. Castro was kind enough to give us some concluding remarks about the findings and future directions:

Most studies that have examined the role of mitochondrial dysfunction in both CFS and FMS patients have been incomplete and contradictory, showing several discrepancies.

According to our results, oxidative stress and mitochondrial bioenergetic dysfunction are common events in CFS and FMS patients that are implicated in the activity and severity of symptoms in both illnesses.

In most instances, CFS and FMS coexist in the same patient. There is a considerable overlap of clinical symptoms between both conditions. We have shown differences in cellular mechanisms and molecular pathways in mitochondria. The implication of both PGC-1 alpha and TFAM has appointed a new path toward the understanding of pathogenesis in CFS and FMS as well as the development of new tools to distinguish one from another.

So as you can see, these findings are exciting and add to the already significant and ever-growing evidence of mitochondrial dysfunction in FM and ME/CFS. This was a fairly small study, looking at 23 CFS patients, 20 FM, and 15 healthy controls. Nonetheless, it reports some useful findings which have promise as legitimate biomarkers for FM and ME/CFS. This is probably the most immediately promising finding here.

More research is needed to build on these findings in larger studies with disease controls and patients should encourage such further research to be undertaken by this group and other groups involved in FM and ME/CFS research.

Source:  Castro-Marrero J, et al. Could mitochondrial dysfunction be a differentiating marker between Chronic Fatigue Syndrome and Fibromyalgia? Antioxidants & Redox Signaling. May 29, 2013. 

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