Authors
Cara Tomas, Joanna L Elson, Victoria Strassheim, Julia L Newton, Mark Walker
Institution
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Publication
PLoS One, 2020 April 10; 15(4):e0231136
Key findings
- Moderately affected (housebound) patients have a mitochondrial impairment
- Severely affected (bedbound) patients have mitochondrial and glycolytic impairments
Comment by ME Research UK
Researchers at Newcastle University have been trying to determine the cause of the severe fatigue and post-exertional malaise experienced by patients with ME/CFS.
ME Research UK has funded several of the team’s projects over the years, with notable findings including a reduction in cellular ATP (energy) levels in ME/CFS patients, and potential issues with AMPK signalling (responsible for regulating energy levels in cells).
In this latest study, the authors reanalysed some of the findings from their previous work, separating the ME/CFS patients into two groups: moderately affected (housebound) and severely affected (bedbound).
They measured respiration rates in blood cells from ME/CFS patients and control subjects, to determine if there was a difference in mitochondrial function and in metabolic pathways such as glycolysis. (Mitochondria are responsible for the majority of energy production in cells, while glycolysis is the process by which glucose is broken down to release energy.)
The investigators found that mitochondrial function was reduced by a similar extent in both the moderately and severely affected ME/CFS patients (compared with the healthy control subjects). Therefore, the reduced mitochondrial function was not associated with disease severity, suggesting that it is a result of ME/CFS and not deconditioning in response to severe symptoms.
Both patient groups also had lower rates of ATP-linked respiration, pointing to a possible defect in ME/CFS patients’ metabolic pathways such as glycolysis and/or the OXPHOS pathways (both key pathways for ATP production and, hence, energy levels). This reduced output was linked to disease severity, with a greater reduction seen in the severely affected group.
In their previous study, the authors had found no difference in glycolysis between controls and ME/CFS patients. However, by separating out the patients into the two groups by disease severity, we can now see that the most severely affected patients do actually appear to have reduced glycolysis levels, while moderately affected patients do not.
So, in summary, this study shows that moderately affected (housebound) patients have a mitochondrial impairment, while those who are severely affected (bedbound) have both mitochondrial and glycolytic impairments.
What does this all mean? The findings show a mitochondrial defect in both moderately and severely affected ME/CFS patients, suggesting that the post-exertional malaise and fatigue seen in ME/CFS may be caused by a defect in – or related to – one of the metabolic pathways such as glycolysis or OXPHOS.
The study also highlights the importance of conducting research into the most severely affected ME/CFS patients, where possible. This has not been seen much before now, and there are multiple challenges in involving this group in research, as the Newcastle team has explored in another branch of their work.
Potential next steps would be to test these methods in other diseases with symptoms of severe fatigue, to determine if the findings are a result of the symptoms (fatigue) or the underlying disease (ME/CFS).
Abstract
Myalgic encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) has been associated with abnormalities in mitochondrial function. In this study we have analysed previous bioenergetics data in peripheral blood mononuclear cells (PBMCs) using new techniques in order to further elucidate differences between ME/CFS and healthy control cohorts. We stratified our ME/CFS cohort into two individual cohorts representing moderately and severely affected patients in order to determine if disease severity is associated with bioenergetic function in PBMCs. Both ME/CFS cohorts showed reduced mitochondrial function when compared to a healthy control cohort. This shows that disease severity does not correlate with mitochondrial function and even those with a moderate form of the disease show evidence of mitochondrial dysfunction. Equations devised by another research group have enabled us to calculate ATP-linked respiration rates and glycolytic parameters. Parameters of glycolytic function were calculated by taking into account respiratory acidification. This revealed severely affected ME/CFS patients to have higher rates of respiratory acidification and showed the importance of accounting for respiratory acidification when calculating parameters of glycolytic function. Analysis of previously published glycolysis data, after taking into account respiratory acidification, showed severely affected patients have reduced glycolysis compared to moderately affected patients and healthy controls. Rates of ATP-linked respiration were also calculated and shown to be lower in both ME/CFS cohorts. This study shows that severely affected patients have mitochondrial and glycolytic impairments, which sets them apart from moderately affected patients who only have mitochondrial impairment. This may explain why these patients present with a more severe phenotype.
Funding
This study was funded by an ME Research UK grant to MW. Additional funding awarded to JLN from The Medical Research Council, Action for ME, and the ME Association was also used to fund this study.
