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 – by Andrew Gladman.
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?
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.
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.[appeal]?