In Brief: Mitochondria and ME

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The third in a series of short articles attempting to explain the science behind fairly common topics and exploring how they relate to ME. This time the topic is Mitochondria – byAndrew Gladman.
A single mitochondrion - hundreds of these organelles exist within each single cell of the body.

Over the years it is fairly safe to say that finding consistent physiological abnormalities in ME has proven difficult for researchers, and that this has likely reinforced the notion that ME is largely a psychological disease – an error which only in recent years is being shaken off.

One area that has shown consistent interest is the mitochondria, with many researchers acknowledging or suspecting mitochondrial dysfunction as a real physiological problem. Some even believe it could play a central role in the pathology of ME.

What are the mitochondria?

The mitochondria are a membrane-bound organelle residing inside the cell. Because the mitochondria themselves have a membrane surrounding them, they could be simply described as a smaller uni-function cell within a larger multi-function cell.

The mitochondria are an integral part of the cell machinery and, to use an analogy, if the cell can be considered a factory then the mitochondria serve as the power generator or engine room – providing the power required for all other cellular processes in the form of a small molecule known as adenosine triphosphate (ATP).

ATP is generally known as the currency of energy within the body, storing energy in the short term and transferring it when required. The majority of energy is produced through a process known as aerobic respiration, and which is based almost entirely within the mitochondria.

The mitochondria consist of two membranes, one inside the other - with the inner one being highly folded in on itself. Within the centre of the mitochondrion (inside both membranes) there exists a circular loop of DNA which codes for the mitochondrial enzymes and proteins which are required for the processes of respiration that occur within the mitochondria.

There also exists some small ribosomes, which are often described as molecular machines that work with the mitochondrial DNA to produce these proteins - if the DNA can be considered the instructions for the protein construction then the ribosomes are the machines in which the construction takes place.

The mitochondria itself has become a great topic of discussion and debate with regard to its origins and the mechanism by which it produces ATP. Today, it is a commonly held theory that the mitochondria was originally a separate organism hundreds of millions of years ago, solidifying my previous analogy of the mitochondria as a small cell within a larger cell!

By chance a mitochondrion was taken up into the cells of the primordial ancestors of all higher and complex life, and, instead of being destroyed, the two organisms evolved symbiotically, both receiving an advantage from the other, until eventually the mitochondria became fully integrated into the cell and unable to survive outside of it. This is known as the endosymbiont hypothesis. The theory is supported by the similarity of the mitochondria to some bacteria that still exist today and because mitochondria have their own genetic material.

What role does the mitochondrion play in respiration?
Video explaining the process of cellular respiration.

Prior to the 1960's it was commonly known that ATP was the currency of energy and that it was produced by the mitochondria, but it was not known how the ATP came into being.

It was initially believed that a simple series of chemical reactions produced ATP as a product - a process known as substrate level-phosphorylation. However in 1961 Dr. Peter Mitchell, a biochemist, proposed the chemiosmotic hypothesis which is the generally accepted theory today.

However, despite this theory being commonly taught and held in high regard, it was initially met with much criticism and disbelief from his peers, indicating just how much evidence is required before a hypothesis such as this can really become accepted in mainstream science.

To summarise this important theory, it is helpful to have an understanding of the process of respiration, and this can simply be broken down into the following four stages:
  • Glycolysis - Glucose, essentially the fuel extracted from our food, in the cell is broken down in numerous stages until two molecules of pyruvate are formed.
  • The Link Reaction - converts the products of glycolysis into the initial reactants required for the krebs cycle.
  • The Krebs Cycle - a multi-stepped reaction that forms a cycle, with the initial reactant being the same as the final product.
  • Oxidative phosphorlyation - the final process and the only one where oxygen is used. Several products of the other three stages are used along with oxygen to produce the vast majority of ATP.
Each are further divided into many steps however the detail of each step is not required to understand the concept.

The first of these stages, glycolysis, doesn't occur within any organelle and simply takes place in the liquid filling the cell, known as cytoplasm. During this stage there is in fact some production of ATP, however only a very little amount, and this is used in the absence of oxygen as this stage forms the basis of anaerobic respiration with lactic acid also generated as a by-product.

Glycolysis is thought to be the most ancient method of energy production and is common to all living organisms, evolving long before the mitochondrion entered primordial cells. The end-product of glycolysis, pyruvate, is then transported into the mitochondrion and the new two stages, the link reactions and the Krebs Cycle, both occur within the fluid filling the mitochondrion, often described as the mitochondrial matrix.

The Krebs Cycle, so named after the man who described the process in detail, Dr Hans Krebs, is a step-by-step series of reactions which loop around so that the final product of the process of reaction is the same as the initial reactant hence the cycle keeps going. In a similar fashion to glycolysis a small number of ATP molecules are also produced.
ATP synthase enzyme, the enzyme embedded in the inner membrane of the mitochondrion. The upper portion spins when protons flow through the enzyme producing ATP. By Alex.X (enWiki (PDB.org for coordinate)) [GFDL or CC-BY-SA-3.0], via Wikimedia Commons

However, the true purpose of both glycolysis and the Krebs Cycle is to produce a molecule such as NADH and FADH2. These carry energy in the form of electrons and protons to the electron transport chain, a simple series of proteins embedded in the mitochondrial membrane.

These energy carriers are produced as a by-product of many of the reactions involved in both these reaction processes. It appears somewhat difficult to understand why this might be important, however both the electrons and protons become very important in the final stage of respiration, oxidative phosphorylation.

Oxidative phosphorylation is the process advanced by Dr Mitchell and he described it quite eloquently:

“It works much like a hydroelectric dam. The energy released by the oxidation of food (via a series of steps) is used to pump protons across a membrane — the dam — creating, in effect, a proton reservoir on one side of the membrane. The flow of protons through amazing protein turbines embedded in this membrane powers the synthesis of ATP in much the same way that the flow of water through mechanized turbines generates electricity.”

For this to work there are two isolated areas within the mitochondria – hence why is has two membranes. An area between the two membrane, known fittingly as the intermembrane space, has a high concentration of H+ molecules and one has a much lower concentration of H+ molecules. This is termed an electro-chemical gradient for the simple reason that one side has more positively charged chemical molecules than the other.

The electron in the energy carrier is transferred into the proteins of the electron transport chain and as the electron is passed from protein to protein, the energy released is used to pump the protons (H+) into the intermembrane space, forming a lake of protons ready to flow through the dam, thus allowing for the production of ATP. The H+ then flows through the ATP synthase enzyme (the dam) thus spinning the enzyme head and producing the vast majority of ATP.

Why are the mitochondria important in ME?

In the previous sections I explained the processes involved in respiration and where the mitochondrion fits into this picture. Given this information and the integral role that it plays in this vital process, it is fairly easy to understand why any dysfunction or deregulation within this organelle can spell problems for the patient and how such an occurrence has the potential to explain the symptoms that ME patients suffer on a day to day basis.

One of researchers most recognised by patients in this area of mitochondria and ME is Dr Sarah Myhill who has published several papers on the topic and also talks about mitochondria on her website. Fundamentally, the hypothesis proposed by Dr. Myhill is best described in her own words:

“The job of mitochondria is to supply energy in the form of ATP (adenosine triphosphate). This is the universal currency of energy. It can be used for all sorts of biochemical jobs from muscle contraction to hormone production. When mitochondria fail, this results in poor supply of ATP, so cells go slow because they do not have the energy supply to function at a normal speed. This means that all bodily functions go slow.”

There are problems with regard to this research however, not least the view that the authors have competing interests, and therefore some patients and other researchers do take the claims made and the treatments prescribed with a pinch of salt, at least until more research can be independently carried out.

Other researchers such as Professor Julia Newton have shown through their own research that muscles in patients with ME produce much larger volumes of lactic acid upon stimulation than healthy controls. This implies an underlying problem that could be sourced to the mitochondria and might indicate that anaerobic respiration has to 'pick up the slack' for the ATP requirements of the cell.

Dr Chris Snell is renowned for his work with ME patients with regard to exercise ability and subsequent intolerance, specifically with regard to exercise testing. His work has highlighted the post exercise malaise and reduced functional capability exercise can have on patient performance. Dr Snell's latest research could indicate a possible problem in mitochondrial function.

However, it is worth noting that past studies involving the testing of VO2 MAX and the anaerobic threshold of ME patients have resulted in findings that are dramatically different from results of known diseases involving mitochondrial function, and whilst Dr Snell's research might indicate there is a problem of exercise intolerance in ME patients, this would appear to contradict the proposed hypothesis of mitochondrial dysfunction as a central mechanism in ME.

Possibly one of the most exciting lines of research is now set to come out of the UK and from a team based in Liverpool and led by Professor Anne McArdle. They are undertaking work using newly developed and ground-breaking mitochondrial analysis techniques in order to better analyse any abnormalities in patient mitochondrial function, and their research will also look at cytokine production in the skeletal muscles of ME patients.

The following quote is taken from the Liverpool University website regarding their ongoing research:

“Scientists have hypothesised that the mitochondria in ME patients could be malfunctioning, significantly reducing the energy supply to the muscle cells that allow the body to carry out its daily activities. The pain and inflammation that follows can cause further mitochondrial abnormalities and so the vicious cycle of events continue.”

Interestingly, both this research and the work by Professor Julia Newton and her team have both been funded in large part by the Medical Research Council.

Given the interest and existing evidence regarding mitochondria and ME, it is clear to me that the mitochondria are very likely to play a role, whether it be directly or indirectly, in the pathology and hence the symptoms of this disease. The evidence however, as in most ME research areas, is somewhat sparse and much of the data has proved unreliable or has not been successfully replicated.

From a personal point of view, it is difficult to place the mitochondria as a central pillar within the pathology of ME, these organelles certainly appear to be adversely affected, hence losing a degree of their function, however it seems likely that this is a downstream result of more widespread dysfunction and dysregulation in other organs and tissues.

Looking ahead, the mitochondria could prove to be one direction for possible symptomatic treatment following further research into the area. However there is much more research to be done and only after each area of interest has been researched thoroughly, can the tangled knot of ME be successfully divided into the numerous strings of which it is composed.

If anyone has any requests or suggestions of topics for future installments be sure to let me know in the comments below.

Next time we explore the vascular system; how it works and why it could be one of the most promising areas of research in ME.


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Comments

I fell very strongly, from my own symptoms, that mitochondrial dysfunction is at the root of what is wrong, not something downstream from it.
My ME is downstream from my mitochondria not working. :p
Every cell, every organ and every system in the body depends on mitochondria working properly.
My every cell, my every organ and (nearly) my every system do not work.o_O
 
Just one wee minor thing of interest missing from this excellent article - which is that the mitochondria are inherited down the female line.
 
Just one wee minor thing of interest missing from this excellent article - which is that the mitochondria are inherited down the female line.

Indeed they are - as an organelle within every cell they are located in the ovum of a mother - the sperm simply serves to combine with the DNA of the ovum and none of its mitochondria are incorporated. Interesting point and one that admittedly I forgot to include although the article was getting pretty long already! Perhaps not entirely relevant but then again we have yet to either confirm or deny whether ME can be passed down through genetic defects etc. The picture is further complicated as despite the mitochondrion having its own DNA, some of the mitochondrial proteins are produced by the normal cell DNA - presumably some of the mitochondrial DNA was incorporated into the cellular DNA millions of years ago.

I fell very strongly, from my own symptoms, that mitochondrial dysfunction is at the root of what is wrong, not something downstream from it.
My ME is downstream from my mitochondria not working. :p
Every cell, every organ and every system in the body depends on mitochondria working properly.
My every cell, my every organ and (nearly) my every system do not work.o_O
It all comes down to that pesky non-homogeneous grouping of ME. For some mitochondria likely play a much more central role however it appears that for the majority mitochondrial issues aren't as paramount as other areas, the trouble is that mitochondria are indeed central to nearly all cellular activity so even a small degree of dysfunction can cause a wide range of seemingly unconnected symptoms. The reason for my personal view of mitochondria not being central to the pathology is simply the lack of evidence and research to support it, although even if it is a downstream problem that isn't to say it could contribute to or even cause many of the ME symptoms. Another interesting point I didn't include was that there are other energy carrying molecules in the body with very specific function such as GTP which is used primarily in the transfer of proteins and chemicals in and out of the nucleus membrane. It just goes to show that the more we look into these things, the more complex it gets!

Glad you liked the article anyway!
 
The proton pump is is a bit of bio-engineering that never fails to impress me.
Every single one of our cells can strip an electron off a molecule.... and keep it off.

Has physics managed to do that yet?:p
 
The proton pump is is a bit of bio-engineering that never fails to impress me.
Every single one of our cells can strip an electron off a molecule.... and keep it off.

Has physics managed to do that yet?:p

It is pretty amazing, a perfect example of the complexity evolution can achieve through small advantageous steps. I always think that it's amazing that a proton motive force and electrochemical gradient have evolved in perfect harmony with the ATP synthase enzyme to convert chemical and electrical energy into kinetic energy and then back into chemical energy, and how this all occurs simply to phosphorylate ADP. It's easy to see why a single problem could cause the whole system to back up and cause a plethora of seemingly unconnected symptoms.

I couldn't speak for physics unfortunately as I never studied it beyond compulsory levels, other than a little mechanics in maths - I studied biology, chemistry and maths. It always seems that we're a step behind evolution though, everything we come up with is always discovered in nature somewhere.
 
I don't like physics myself.
I don't trust electrons when they're not stuck to molecules, or gently stripped off and put tidily away somewhere else.
Mechanical stuff, levers and pulleys and vetors are fine.

Nature is wonderful and far more amazing than any fiction.

But I don't like that electrickery.
 
Nice article, well written. However I think there is more research to suggest mitochondrial dysfunction occurs in ME/CFS.

http://cellfatigue.blogspot.com/2013/04/mitochondrial-dysfunction-in-cfs.html?utm_source=BP_recent
 
Nice article, well written. However I think there is more research to suggest mitochondrial dysfunction occurs in ME/CFS.

http://cellfatigue.blogspot.com/2013/04/mitochondrial-dysfunction-in-cfs.html?utm_source=BP_recent

nice article there - I particularly like the following comment.

"There is now substantial evidence to suggest systemic mitochondrial dysfunction occurs in ME/CFS and underlies symptoms of fatigue. The causes of this dysfunction could be many but likely include impaired blood flow, cofactor depletion (e.g. Co-Q10), oxidative damage and dysregulation by inflammatory signaling"

It sums up quite eloquently that despite mitochondrial dysfunction appearing to be a downstream problem, the symptoms caused by the dysfunction can be incredibly widespread. The next article in the series relates to the cardiovascular system which links quite nicely with mitochondrial dysfunction. Glad you liked the article.
 
Thank-you for writing this article.
I was wondering if about the proposed incidence of ME/CFS and CCSVI and the purported mitochondrial involvement with loss of patency of the tricuspid valve in the heart with resulting venous congestion in the brain and liver.
Do you have any comments regarding this theory? Would limiting the brain's access to oxygenated blood be the cause of orthostatic intolerance? Could brain-fog be related to this and/or failure to clear catabolites etc?
My brain-fog used to double if I had to stand. Again, thanks....brad
 
Thank-you for writing this article.
I was wondering if about the proposed incidence of ME/CFS and CCSVI and the purported mitochondrial involvement with loss of patency of the tricuspid valve in the heart with resulting venous congestion in the brain and liver.
Do you have any comments regarding this theory? Would limiting the brain's access to oxygenated blood be the cause of orthostatic intolerance? Could brain-fog be related to this and/or failure to clear catabolites etc?
My brain-fog used to double if I had to stand. Again, thanks....brad

I have to admit i'm unfamiliar with CCSVI so i wouldn't feel comfortable answering the question without further research unfortunately. I shall look into it and perhaps post a better researched response tomorrow.

With regard to brain-fog however I think it could well be due to dysregulation clearing catabolites within the brain. Only recently I was reading about the glymphatic system, the specialised lymphatic system in the brain which has only very recently begun to be well understood. It is comprised of many channels within the brain that clear catabolites and waste products from the neurones, especially during sleep when glial cells shrink, hence allowing for increased glymphatic flow. It has been been researched in the context of neuro-degenerative diseases and dementia however I think it could well prove to be an interesting line of research for ME, especially given that one of the most common symptoms is headaches/migraines which could stem from such a waste build-up - not to mention that sleep is often disrupted hence not allowing for the standard 'cleaning' of the brain during sleep.

With regard to orthostatic intolerance, I think it stems from a combination of cardiovascular insufficiency as well as autonomic - that being both sympathetic and parasympathetic - dysfunction. These systems are components of the peripheral nervous system therefore I have to question whether lack of oxygen to the brain is a central cause however given the aforementioned glymphatic system, I think damage in this way could potentially explain certain elements of orthostatic intolerance. There is no doubt that the comorbidity of ME and orthostatic intolerance ought to be telling us something is not working as intended in the circulatory and/or nervous system - both topics I intend to explore in future articles. As with everything further research is vital! Thanks for the good questions and I hope these answers give you interesting things to research and postulate on.
 
Mitochondriae don't "just fail", such as by genetically. Given my 100% certainty that this disease is contagious, it's the stealth pathogen that has so far escaped identification, that is the true causal agent. I don't know the scientific process of "why" the mitochondria are damaged and don't function properly, but it is reasonable that it's associated with the invading pathogen. My best guess: it's a yet undiscovered retrovirus, very difficult to find. But it wreaks havoc by "going viral" ; hence the millions of people now infected, and many more to come if this snail's pace of research isn't sped up. We old-timers are starting to lose the ultimate battle more and more.
 
Mitochondriae don't "just fail", such as by genetically. Given my 100% certainty that this disease is contagious, it's the stealth pathogen that has so far escaped identification, that is the true causal agent. I don't know the scientific process of "why" the mitochondria are damaged and don't function properly, but it is reasonable that it's associated with the invading pathogen. My best guess: it's a yet undiscovered retrovirus, very difficult to find. But it wreaks havoc by "going viral" ; hence the millions of people now infected, and many more to come if this snail's pace of research isn't sped up. We old-timers are starting to lose the ultimate battle more and more.

I honestly think the evidence just isn't there for either ME being contagious or a 'stealth pathogen' as you put it. If mitochondrial dysfunction is involved then it is unlikely that such an infectious agent would effect the mitochondria, the sole purpose of a virus at the end of the day is to replicate. I discussed this at some length in my article exploring viruses and I recommend reading that article if viruses are your personal opinion of a causative mechanism - you might enjoy the content. I think that the endless search for viruses has done more harm than good for ME now.

As I've expressed many times previously I believe ME is caused by a genetic defect which could potentially be passed through families. Upon great stress being placed on the immune system the genetic weakness leads to the ongoing diseases process whatever that may be - an analogy I liken it to is spreading petrol in a forest. The spark is the initial virus, infection or stress however once the forest is ablaze there seems little point in searching for the triggering virus which likely plays no role in the ongoing blaze. Whether this blaze is an autoimmune process or otherwise is yet to be seen but I think it's high time that another hypothesis took the lead as the viral hypothesis has proven incorrect for nearly 30 years - if there was something to find, i'm of the opinion that it would have by now.

At the end of the day complex diseases need devious answers and viruses simply do not fit this disease process in my mind, autoimmunity may and I look forward to further research in this area.
 
Good article Andrew yet again!
Your analogy in the above statement is very good.
I think it is good that we have two areas of research happening. Virus/pathogen and autoimmune.
Both areas will help to form the picture and produce biomarkers and analyse what is happening in our bodies. One area of research can end up helping or supporting another if it is quality research.
I would love to see an article about all the top quality research that's happening right now and an analysis of how they may help support our picture and possibly tie up together.
Not all of us can go searching the net or have the education to see how that might happen.
I could do with that help, analysis and information.
That could also promote more donations or spark more people to join ME organisations.
Just a thought :)
 
Nice article, well written. However I think there is more research to suggest mitochondrial dysfunction occurs in ME/CFS.

http://cellfatigue.blogspot.com/2013/04/mitochondrial-dysfunction-in-cfs.html?utm_source=BP_recent
They got another $2 million grant to study a larger cohort which is good.
 
Whose view is it that Myhill et al are not to be considered too seriously because of their "competing" interests? Would like to know whose view and which competing interests, as I am other wise somewhat lost and confused.
 
A helpful essay--many thanks. You probably know the essay from Julia Newton's group, though the first listed author is D.E.J. Jones, "Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome", 2009. This suggests various mechanisms by which the ANS might exert control over the mitochondria--the essay does not use the word, but it seems implicit in how it defines "peripheral muscle."

She also has a great little essay, "Home orthostatic training in chronic fatigue syndrome--a randomized, placebo-controlled feasibility study", 2010. I have been doing this for about 3 months now, and my OI is quite substantially improved, and I think slowly my fatigue is improving too--it is good stuff, and I recommend it, though take care--she talks about a "drop-zone" and you have to make sure that you won't get hurt if you pass out! This simple execise has been shown to cure neurocardiogenc syncope, but I think this was the first essay linking it to ME/CFS. Chris
 
I think OI might have a lot to do with lack of vasoconstriction, (ie, a smooth muscular problem) as well as low blood volume.
 
There isn't one single symptom that cannot be accounted for by the lack of sufficient energy production in the mitochondria.

How much further "downstream" can you get than the mitochondria? :confused:
 
I think OI might have a lot to do with lack of vasoconstriction, (ie, a smooth muscular problem) as well as low blood volume.

There isn't one single symptom that cannot be accounted for by the lack of sufficient energy production in the mitochondria.

How much further "downstream" can you get than the mitochondria? :confused:

From a personal stance I think you're likely getting at something very important in the first quote. Many of the chemicals involved in vasoconstriction and vasodilation have numerous other roles and some influence directly mitochondrial function. As such any dysregulation in the endothelium (the layer of cells that secrete these vasoactive chemicals) could potentially influence mitochondrial function. By downstream, what I mean is that it is likely not the first step of dysfunction occurring - but that is not to say it could be a major part of the disease pathology, to use yet another analogy: If i were to go to the source of a river and pour in gallons of toxins there would be no obersevable problems at that area but downstream all the plants and fish would likely die, the problem started at the very source where i poured in the toxins but the majority of problems occurred much further downstream, you can help the ecosystem by purifying the water downstream but to solve the problem you'd have to stop the pollution at the river source and I think most diseases work like this. I plan to write a lot more in my next article regarding vasoconstriction and vasodilation, the endothelium and the cardiovascular system as a whole which will be worth a read if you're interested in that area of ME research.