Cara Tomas C, Brown A, Strassheim V, Elson J, Newton J, Manning P
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS. Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients. A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls. Seven key parameters of OXPHOS were calculated: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, non-mitochondrial respiration, and coupling efficiency. While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study (p0.003). The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.
The Medical Research Council, Action for ME, ME Research UK, the ME association and the Newcastle Molecular Pathology Node.
Comment by ME Research UK
Bioenergetics refers to the exchange and transformation of energy in the cells of the human body. It involves a number of processes including cellular metabolism, and often centres around a molecule called adenosine triphosphate (ATP), known as the energy currency of the body.
It is not surprising, therefore, that researchers are interested in whether abnormalities in bioenergetic function are responsible for the severe fatigue experienced by people with ME/CFS, and studies have looked at areas such as mitochondrial dysfunction, AMPK activation, oxidative stress and muscle cell acidosis.
The mitochondria are often referred to as the power plants of the body because they are responsible for generating ATP, and these crucial cellular structures have attracted particular attention in ME/CFS.
As part of a programme of research funded by ME Research UK, Prof. Julia Newton and colleagues at Newcastle University have been exploring two aspects of mitochondrial function, and the results were recently published in the journal PLoS One.
Using blood samples obtained from 52 patients with CFS, as defined by the Fukuda Diagnostic Criteria, and 35 healthy control subjects, the researchers looked at two energy-producing pathways within the mitochondria.
Oxidative phosphorylation is the process by which nutrients are oxidised (changed by the addition of oxygen) to release energy which is used to produce ATP. The team measured a number of aspects of this pathway, and found that most were reduced in the ME/CFS patients compared with the healthy controls.
In particular, maximal mitochondrial respiration was consistently lower in the patient group, indicating that under physiological stress these cells would be less able to increase their respiration rate to compensate, and therefore unable to fulfil energy demands. However, the researchers make a point of emphasising that it is not clear whether these changes are a cause or consequence of ME/CFS.
The team also looked at glycolytic function, which is the process by which glucose is broken down into ATP. Interestingly, there were no differences between ME/CFS patients and healthy controls, which contrasts with the findings of other studies, although this may be because of the relatively small sample size.
The results of this study have shed more light onto the abnormalities in bioenergetics that are characteristic of ME/CFS, particularly the impaired oxidative phosphorylation pathway which may help to explain the symptoms of fatigue. And they also suggest new lines of research that may help get us closer to a fuller explanation.