Dr Eleanor Roberts
Our previous article discussed mitochondria structure, function and metabolism; here we put some of that knowledge into the context of ME/CFS.
As anyone with ME/CFS can testify, the reason you can’t lift, push or carry the things you once lifted, pushed or carried with ease is because your muscles seem drained of all energy, similar to the feeling you used to get pushing for that last rep in the gym or running until you gloriously drop. This has spurred researchers to investigate whether disruption in adenosine triphosphate (ATP) production by mitochondria is the key behind some of the core features of ME/CFS: fatigue and post-exertional malaise.
While much work has been carried out in this field, coming up with an overall “this is what’s going on in mitochondria in ME/CFS” statement is hampered by individual studies having different ways of examining mitochondria in differing cell types using samples from people with ME/CFS with differing levels of function, diagnostic criteria and years of illness, among other variables. These factors may greatly impact study results and this highlights the huge unmet need for large, multi-centre investigations using the same protocol and participant criteria to examine one of the basic underlying theories of what causes the often disabling symptoms of ME/CFS.
In a bid to rationalise the findings of a number of studies, a systematic review by Dr Sean Holden and colleagues included only studies published in English from 1994−2020 that investigated mitochondria in adults with diagnosed ME/CFS (according to Fukuda, Canadian Consensus, International Consensus or Institute of Medicine Criteria) compared to healthy controls, carried out using validated methods of mitochondria analysis.1 Using these search criteria, they found 19 studies, which will be discussed here.
These are by no means the only studies investigating mitochondria in ME/CFS and non-inclusion of studies that did not fit their criteria does not mean those study results are invalid. It is also of note that most of the studies included in this review investigated only immune system cells from the blood, presumably as these cells are easy to access and work with. This means that results must be viewed with the idea that changes found in one cell type may not necessarily occur in all cell types.
Genetic defects in mitochondria
Although there are currently no indications of a frank mitochondrial disorder in ME/CFS, such as having differences in the number of copies of mitochondrial DNA,2 differences have been found according to mitochondrial DNA haplogroups (subtypes of mitochondrial DNA related to ancestry).3 While one study didn’t distinguish between people with ME/CFS and healthy controls according to haplogroup, they did find that those with subtypes H, J and U but not K or T had greater appearance and severity of some ME/CFS symptoms including joint pain, bloating and “dead/heavy feeling after exercise.” This indicates that while haplogroups do not predispose a person to develop ME/CFS, they may play a role in symptom array. Of note though, this study only had enough participants to examine people of European origin, a study examining ME/CFS mitochondrial haplotypes on a global scale could find other haplotypes are also involved in ME/CFS symptoms.3
While DNA may be intact, how it is ‘expressed’ (i.e., what proteins are being made from particular DNA sections) was shown to be different in a study of peripheral blood mononuclear cells (PBMCs, consisting of lymphocytes and monocytes) of people with ME/CFS. Compared to healthy controls, there was increased expression of genes involved in oxidative stress and decreased expression of genes involved in metabolic pathways, both of which the authors postulated could be related to mitochondrial dysfunction.4
The structure of mitochondria
Mitochondria are dynamic organelles whose structure and number can change according to need.5 It could be postulated that people with ME/CFS simply have fewer mitochondria, but one study examining lymphoblasts (pre-cursors to B and T cells) found no change in mitochondrial mass in people with ME/CFS.6 Even if mitochondrial number isn’t different, one study of mitochondrial structural changes in people with ME/CFS showed irregular fusion and branching of cristae, where energy production is greatest.7 However, other studies, such as one of muscle mitochondria, have not found overall structural changes.8
Homing in to the mechanism of energy production itself, increases have been shown in the levels of proteins that make up the electron transfer chain (ETC) complexes in immortalised lymphocytes6 and PBMCs.9 As some ‘stress response’ proteins were also increased in one of these studies, the authors suggested that elevations in these indices of mitochondrial activity could be to potentially harmful levels in people with ME/CFS.6 The other study also found decreases in proteins involved in mitochondria assembly and reduction-oxidation regulation.9
In the same way a factory building can be structurally sound on the outside but production is falling apart inside, even if the structure of mitochondria is not drastically altered in people with ME/CFSA, this doesn’t mean function, in terms of energy production, is okay. Indeed, one study that investigated overall mitochondria function and efficacy in neutrophils found it to be significantly lower in people with ME/CFS compared to controls, correlating with ME/CFS severity.10
Some studies have found differences in particular aspects of respiratory function, for instance, maximal respiration was found significantly lower in PMBCs of people with ME/CFS compared to controls,11 although others have not found respiratory differences when looking at natural killer cells.12 Intriguingly, the latter may be explained by another study that showed that in lymphoblasts of people with ME/CFS there was a higher rate and peak of oxygen consumption at Complex I but a lower rate at ATP synthase (Complex V), so that while energy production overall was the same, it was, they postulated, due to the former compensating for the latter.6
As discussed previously, the mitochondrial membrane potential (where hydrogen ions [H+ or protons] accumulate at a higher level in the intermembrane space than the matrix) is the key driving force in production of the energy containing molecule ATP. Studies examining lymphoblasts6 and CD8+ (cytotoxic) T cells,13 have found this membrane potential to be decreased in people with ME/CFS. This was postulated in the latter study to be related to T cell exhaustion, as has been shown in some chronic viral infections.14
This membrane potential decrease may be related to increases in proton leak (where protons return to the matrix at places other than via ATP synthase), as shown by two studies in lymphoblasts, indicating decreased mitochondrial efficiency.6,15 However, the opposite, decreased proton leak compared to healthy controls, was found in one study of PBMCs during a mitochondrial stress test11 and another in CD8+ cells.13 These results again indicate how hard it is to compare study findings as changes found in people with ME/CFS may be limited to very specific cell types (for instance, the study that found differences in CD8+ cells didn’t find these differences in CD4+ T-helper cells13) and only under certain conditions that increase the demand for energy from mitochondria.
It is also possible that mitochondria are functioning normally in people with ME/CFS but upstream processes are not working properly. A study of glycolysis, which creates the pyruvate turned into energy in mitochondria, found reductions in this process in CD8+ and CD4+ T cells in people with ME/CFS when the cells were at rest and (in CD8+ cells) when they were stimulated.13 Another study investigating natural killer cells found a decrease in glycolytic reserve, a measure of a cell’s ability to increase the amount of glucose converted into pyruvate.12
One way of investigating how mitochondria are functioning is by looking at the molecules used for energy production and the resulting ATP. Metabolite changes may occur at one or many levels of energy generation. This is reflected in studies that have found differences in molecules related to glycolysis – such as significantly decreased16 or increased17 levels of plasma glucose and decreased pyruvate in urine17 – and the tricarboxylic acid cycle (TCA) – including altered plasma amino acid ratios18 and decreased levels19 and decreased oxaloacetate.16
Differences between people with ME/CFS and healthy controls have also been found when examining levels of ATP itself. One study of blood plasma found decreases in both ATP and adenosine diphosphate (ADP)16 and two studies examining PBMCs found decreased ATP production.11,20 One of these studies also found differences between ME/CFS and healthy control participants when mitochondria were stressed and put in conditions of either high or low glucose availability.11 On finding decreased ATP production in activated CD8+ cells, another study postulated that “ME CD8+ T cells may be less able to induce metabolism following activation.”13
On the other hand, although decreased ATP synthesis activation in lymphoblasts was found in one investigation, differences in steady state ATP levels were not shown, potentially due to compensation by elements of the ETC.6 Finally, a study investigating ATP levels in the brain using imaging as opposed to extracting mitochondria did not show any differences.21
Coenzyme Q10 is a vital part of the ETC and significantly lower levels of this molecule have been found in PBMCs in people with ME/CFS,20 correlating with symptoms.22 This is of interest as Coenzyme Q10 is being investigated as a supplement for people with ME/CFS to alleviate fatigue.23 Two studies by the same group found increases in levels of several enzymes involved in the TCA cycle and other energy-related mitochondrial pathways.6,24 In the first of these studies, this enzyme increase was accompanied by a decrease in ATP synthase efficiency so was postulated to be a compensatory mechanism to try to maintain ATP levels.6
Overall, these findings strongly suggest mitochondrial disruption in people with ME/CFS. This may be due more to problems in energy production pathways than to large genetic or structural faults in mitochondria. Fitting with the experience of people with ME/CFS, such problems seem to be exacerbated, or manifest, when mitochondria are ‘stressed.’
Holden et al. A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease. Journal of Translational Medicine 2020;18:290. Accessed May 2021. Available at: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02452-3.
For a more in-depth look at mitochondria in ME/CFS, this review, though scientifically very intricate, examines many more studies than those included here: Anderson & Maes. Mitochondria and immunity in chronic fatigue syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2020;103:109976. Doi: 10.1016/j.pnpbp.2020.109976 (copies can be requested from the authors).
- Holden, S.; Maksoud, R.; Eaton-Fitch, N.; Cabanas, H.; Staines, D.; Marshall-Gradisnik, S. A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease. J Transl Med 2020, 18, 290.
- Venter, M.; Tomas, C.; Pienaar, I. S.; Strassheim, V.; Erasmus, E.; Ng, W. F.; Howell, N.; Newton, J. L.; Van der Westhuizen, F. H.; Elson, J. L. MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants. Sci Rep 2019, 9, 2914.
- Billing-Ross, P.; Germain, A.; Ye, K.; Keinan, A.; Gu, Z.; Hanson, M. R. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med 2016, 14, 19.
- Sweetman, E.; Ryan, M.; Edgar, C.; MacKay, A.; Vallings, R.; Tate, W. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int J Immunopathol Pharmacol 2019, 33, 2058738418820402.
- Youle, R. J.; van der Bliek, A. M. Mitochondrial fission, fusion, and stress. Science 2012, 337, 1062-1065.
- Missailidis, D.; Annesley, S. J.; Allan, C. Y.; Sanislav, O.; Lidbury, B. A.; Lewis, D. P.; Fisher, P. R. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci 2020, 21.
- Behan, W. M.; More, I. A.; Behan, P. O. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol 1991, 83, 61-65.
- Plioplys, A. V.; Plioplys, S. Electron-microscopic investigation of muscle mitochondria in chronic fatigue syndrome. Neuropsychobiology 1995, 32, 175-181.
- Sweetman, E.; Kleffmann, T.; Edgar, C.; de Lange, M.; Vallings, R.; Tate, W. A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med 2020, 18, 365.
- Myhill, S.; Booth, N. E.; McLaren-Howard, J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2009, 2, 1-16.
- Tomas, C.; Brown, A.; Strassheim, V.; Elson, J. L.; Newton, J.; Manning, P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS One 2017, 12, e0186802.
- Nguyen, T.; Staines, D.; Johnston, S.; Marshall-Gradisnik, S. Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/ chronic fatigue syndrome patients: A preliminary investigation. Asian Pac J Allergy Immunol 2019, 37, 102-108.
- Mandarano, A. H.; Maya, J.; Giloteaux, L.; Peterson, D. L.; Maynard, M.; Gottschalk, C. G.; Hanson, M. R. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest 2020, 130, 1491-1505.
- Schurich, A.; Pallett, L. J.; Jajbhay, D.; Wijngaarden, J.; Otano, I.; Gill, U. S.; Hansi, N.; Kennedy, P. T.; Nastouli, E.; Gilson, R.; Frezza, C.; Henson, S. M.; Maini, M. K. Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host. Cell Rep 2016, 16, 1243-1252.
- Missailidis, D.; Sanislav, O.; Allan, C. Y.; Annesley, S. J.; Fisher, P. R. Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2020, 21.
- Germain, A.; Ruppert, D.; Levine, S. M.; Hanson, M. R. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst 2017, 13, 371-379.
- Armstrong, C. W.; McGregor, N. R.; Lewis, D. P.; Butt, H. L.; Gooley, P. R. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics 2015, 11, 1626-1639.
- Yamano, E.; Sugimoto, M.; Hirayama, A.; Kume, S.; Yamato, M.; Jin, G.; Tajima, S.; Goda, N.; Iwai, K.; Fukuda, S.; Yamaguti, K.; Kuratsune, H.; Soga, T.; Watanabe, Y.; Kataoka, Y. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep 2016, 6, 34990.
- Fluge, Ø.; Mella, O.; Bruland, O.; Risa, K.; Dyrstad, S. E.; Alme, K.; Rekeland, I. G.; Sapkota, D.; Røsland, G. V.; Fosså, A.; Ktoridou-Valen, I.; Lunde, S.; Sørland, K.; Lien, K.; Herder, I.; Thürmer, H.; Gotaas, M. E.; Baranowska, K. A.; Bohnen, L. M.; Schäfer, C.; McCann, A.; Sommerfelt, K.; Helgeland, L.; Ueland, P. M.; Dahl, O.; Tronstad, K. J. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight 2016, 1, e89376.
- Castro-Marrero, J.; Cordero, M. D.; Sáez-Francas, N.; Jimenez-Gutierrez, C.; Aguilar-Montilla, F. J.; Aliste, L.; Alegre-Martin, J. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal 2013, 19, 1855-1860.
- Shungu, D. C.; Weiduschat, N.; Murrough, J. W.; Mao, X.; Pillemer, S.; Dyke, J. P.; Medow, M. S.; Natelson, B. H.; Stewart, J. M.; Mathew, S. J. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 2012, 25, 1073-1087.
- Maes, M.; Mihaylova, I.; Kubera, M.; Uytterhoeven, M.; Vrydags, N.; Bosmans, E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett 2009, 30, 470-476.
- Castro-Marrero, J.; Sáez-Francàs, N.; Segundo, M. J.; Calvo, N.; Faro, M.; Aliste, L.; Fernández de Sevilla, T.; Alegre, J. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome – A randomized, controlled, double-blind trial. Clin Nutr 2016, 35, 826-834.
- Missailidis, D.; Sanislav, O.; Allan, C. Y.; Smith, P. K.; Annesley, S. J.; Fisher, P. R. Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts. Int J Mol Sci 2021, 22.