Researchers
Jente Van Campenhout, Yanthe Buntinx, Huan-Yu Xiong, Arne Wyns, Andrea Polli, Jo Nijs, Joeri L. Aerts, Thessa Laeremans, Jolien Hendrix
Institution
Pain in Motion Research Group, Vrije Universiteit Brussel, Brussels, Belgium
Publication
Biomolecules, 2025 March 1; 15(3):357
Funding
ME Research UK with the financial support of the Fred and Joan Davies Bequest, and Fonds Wetenschappelijk Onderzoek.
Background
Jente Van Campenhout is a PhD student at Vrije Universiteit Brussel, whose research looking at links between mitochondrial function and the autonomic nervous system in ME/CFS is funded by ME Research UK. In this review, Jente summarises the evidence connecting energy metabolism (the process of energy production and utilisation in the body) and dysfunction of the immune system in people with ME/CFS.
Findings from existing research on this topic are complex, and it is challenging to make comparisons between studies because of the different methods used, while the diversity of people with ME/CFS also makes it difficult to draw conclusions from the results of several studies. Despite this, Jente and the team have identified several key areas of interest.
Energy metabolism
Mitochondrial dysfunction in ME/CFS
The mitochondria are often known as the powerhouses of the cells in the body. They are responsible for producing the energy – adenosine triphosphate (ATP) – required for many cellular functions, which in turn drive critical processes in the body, such as muscle contraction.
Jente and colleagues describe decreased ATP production as a “hallmark feature” of ME/CFS. The authors also note that, in people with ME/CFS, the ability of the mitochondria to meet increased energy demands – such as those during physical or cognitive exertion – has been found to be impaired, particularly in those with severe ME/CFS.
The researchers state that, in people with ME/CFS, the inability of cells to adapt to this increased energy demand leaves them “vulnerable to energy crises under stress or exertion and likely contributing to fatigue”.
Oxidative and nitrosative stress
During the process of energy production, mitochondria produce highly reactive oxygen molecules known as reactive oxygen species (ROS). While ROS play a key role in the regulation of cell function, excessive levels can cause damage to cells and tissues.
ROS are normally kept under control by natural processes which remove them from them the circulation, but when an imbalance occurs ROS can be left to build up and cause damage in the body – a state known as oxidative stress.
Oxidative stress has been linked to many diseases, including Alzheimer’s disease, cardiovascular disease and cancer, and it has also been associated with ME/CFS. In fact, findings suggest that the “normal processes controlling free radicals are not working properly in patients with ME/CFS”.
Interestingly, the authors highlight that nitrosative stress – which occurs when reactive nitrogen species build up in the body – has also been identified in people with ME/CFS. Like oxidative stress, nitrosative stress has been linked to cell damage and disease.
Links between dysregulated energy metabolism and symptoms of ME/CFS
Highlighted in the review is the “strong correlation” between mitochondrial dysfunction and ME/CFS symptoms.
The authors note that, in people with ME/CFS, fatigue has been linked to two potential biomarkers of mitochondrial dysfunction: carnitine and Coenzyme Q10. These compounds are essential for both energy metabolism and ensuring that ROS levels do not build up in the cell.
They also highlight that post-exertional malaise (PEM) – said to be the cardinal feature of ME/CFS – may stem from metabolic and mitochondrial dysfunction.
Additionally, research suggests that there may be an earlier switch to less efficient methods of energy production in people with ME/CFS.
Immune dysfunction in ME/CFS
The immune system protects the body from invading infectious agents such as viruses and bacteria (called pathogens). Immune system dysfunction – where the immune system is not functioning as it should – is seen in diseases such as multiple sclerosis and rheumatoid arthritis. Researchers also think that immune system dysfunction may play a role in ME/CFS.
In the review, two key processes that impair immune cell functioning are highlighted and linked with ME/CFS: immune senescence and immune exhaustion.
Immune senescence
Senescence is the process of cellular aging brought on by stress or as a person gets older. Immune cell senescence leads to the gradual deterioration of the immune system, reducing the body’s capacity to fight infection.
Research has linked immune senescence with sleep disturbances and chronic stress – both of which, the reviewers state, are key features of ME/CFS. Despite this, no study has extensively investigated immune senescence in the context of ME/CFS.
Immune exhaustion
Immune exhaustion is a specific type of dysfunction within the immune system that leads to a progressive loss of function in the cells of the body that help fight infection (lymphocytes) – especially T cells.
Immune exhaustion is said to be driven by prolonged immune activation, such as during chronic viral infections or cancer, and has been linked to ME/CFS in research. Despite this, no clear association has been established between immune cell exhaustion and ME/CFS symptoms.
Interestingly, the authors of the review note that one of the key features of immune exhaustion is metabolic dysfunction.
The metabolic-immune link in ME/CFS
Research has found that mitochondria and energy metabolism play a key role in the immune response. Therefore, mitochondrial dysfunction can impair immune cell function and lead to increased susceptibility to infections.
Conversely, the immune system plays a critical role in shaping energy metabolism and mitochondrial function. In fact, ongoing activation of the immune system leads to metabolic dysregulation and can increase the production of ROS leading to oxidative stress.
The link between the immune system and metabolic dysregulation has been recognised as a continuous cycle where information is exchanged in both directions – a “bidirectional feedback loop” which plays a role in aging and diseases such as Parkinson’s Disease, and potentially ME/CFS.
It is thought that the interplay between the two systems exacerbates disease symptoms and leads to a self-perpetuating cycle of dysfunction.
Conclusion
This article highlights the interplay between mitochondrial dysfunction and immune dysregulation in ME/CFS – particularly immune exhaustion, chronic inflammation and oxidative stress. However, more research is needed to investigate the potential role of immune senescence in people with ME/CFS.
In the conclusion, the authors state that “conflicting results across studies, methodological variability, differences in diagnostic criteria, and variations in patient cohorts underscore the need for standardised research approaches”.
Also highlighted is the need for studies that follow large groups of people with ME/CFS over time – these groups must represent the diversity of people with the disease.
