Sunday, 28 April 2013

Mitochondrial dysfunction in CFS: the emerging elephant?

The mitochondrion (click to enlarge)
The central symptom in CFS is profound fatigue, yet the origins and mechanisms underlying this fatigue are still contentious. Psychological, sensory/neural and cellular/mitochondrial processes have been considered. Of these the potential role of cellular energy failure and mitochondrial dysfunction has attracted increasing interest and now underpins several metabolic and inflammatory models of CFS 1–4. Mitochondria house the molecular machinery which mediates aerobic energy metabolism in animal cells, enabling the highly efficient oxygen-dependent production of ATP: the major biological energy molecule. Mitochondrial dysfunction therefore provides a powerful explanation for fatigue in CFS. Many findings are now consistent with this rationale and will be briefly reviewed below.

In the muscles
Research into energy metabolism in CFS properly started back in the early-mid ‘90s 5 and has slowly grown and diversified since. Early studies (pre-2000) looked at muscle tissue in CFS. Several of these found evidence of altered energy metabolism in skeletal muscle in response to exercise in CFS patients (for review see 5). Findings included reduced oxidative metabolism, ATP depletion and increased lactate production 6–9. In addition mitochondrial abnormalities and changes to mtDNA were found in CFS muscle tissue 10; whilst not in another study 11. More recently CFS patients were reported to have altered muscle excitability and increased oxidative stress in response to exercise 12,13. Research by another group further implicates a state of profoundly altered bioenergetic function in CFS patients in response to exercise, including findings of increased acidosis and a co-association between skeletal muscle and cardiac bioenergetic abnormalities 14,15.

In the blood
Recent research into CFS has seen studies assessing mitochondrial function via several blood cell-types. McLaren-Howard and colleagues have found that mitochondrial dysfunction in neutrophils correlates fatigue in CFS 16–18. These studies further implicated altered TL protein function, co-factor insufficiency and toxin accumulation. Peripheral blood mononuclear cells (PBMC) have been used by other teams. An early study on PBMCs from CFS patients found changes in gene expression suggesting perturbed mitochondrial function 19. A later study by another group found that ATP resynthesis was decreased in PBMCs from CFS patients; findings suggested that this was not caused by a defect in the enzyme complexes catalysing oxidative phosphorylation, but in another factor 20. This year another study on PBMCs has reported that ATP and Co-Q10 levels are decreased whilst lipid peroxidation (i.e. oxidative stress) is increased in CFS (and FM) 21.

In the brain
There is now also evidence for brain energy dysfunction in CFS. Recent in vivo MRSI studies by Shungu et al have found increased cerebral spinal fluid (CSF) lactate in CFS (and MDD) 22–24. Lactate, which can accumulate when aerobic energy metabolism fails, correlated with symptoms of fatigue in CFS. Increased lactate levels also inversely correlated to those of cortical glutathione (GSH), the major cellular antioxidant in the body, thus linking oxidative stress with energy dysfunction in the brain in CFS 24.

Bioenergetic nutrients and cofactors
Other studies assessing nutritional and bioenergetic cofactors have provided further indirect evidence of mitochondrial dysfunction in CFS. Several studies have found lowered blood levels of carnitine derivatives 25–29 and decreased acetyl-carnitine brain uptake in CFS 30; whilst a couple of other studies failed to find any changes in blood levels 31,32. Carnitine supplementation was also reported to improve fatigue in CFS patients 33,34. Low Co-Q10 levels in PBMCs 21 and serum have been reported in CFS 35 and correlate with illness severity 36. Another bioenergetic factor, magnesium, has also been reported to be deficient in CFS 35,37. Treatment with NADH was been found to be beneficial in a couple of studies 38,39, whilst ineffective in another 40. A coupled of unblinded studies reported benefit from D-ribose supplementation 41,42. Changes to the make-up of the mitochondrial membrane are also implicated in CFS 43,44 and in a small study treatment aimed at restoring membrane integrity (lipid replacement therapy, LRT) significantly decreased fatigue in CFS patients 44.

Conclusion
There is now substantial evidence to suggest systemic mitochondrial dysfunction occurs in ME/CFS and underlies symptoms of fatigue. The causes of this dysfunction could be many but likely include impaired blood flow, cofactor depletion (e.g. Co-Q10), oxidative damage and dysregulation by inflammatory signaling 1–4. It is further worth noting that mitochondrial dysfunction is also not inconsistent with sensory-related findings in CFS 45–47. New research is desperately required to provide further clarification of the changes to energy metabolism occurring in ME/CFS. Several of the research teams above may release more work in this area this year. For example Dr. Newton and colleagues have more muscle studies in the pipeline. Dr. Shungu and colleges have won a $2 million grant from the NIH to further their brain studies with larger cohorts. To date, research implicating a cellular basis for fatigue in CFS has been poorly covered by mainstream media (including wiki) and is not recognised by public health institutions, as the evidence matures hopefully this will change.


References
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15.        Jones, D. E. J. et al. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. European journal of clinical investigation 42, 186–94 (2012).
16.        Myhill, S., Booth, N. E. & McLaren-Howard, J. Chronic fatigue syndrome and mitochondrial dysfunction. International journal of clinical and experimental medicine 2, 1–16 (2009).
17.        Myhill, S., Booth, N. E. & Mclaren-howard, J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) – a clinical audit. International journal of clinical and experimental medicine 6, 1–15 (2013).
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19.        Kaushik, N. et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. Journal of clinical pathology 58, 826–32 (2005).
20.        Vermeulen, R. C. W., Kurk, R. M., Visser, F. C., Sluiter, W. & Scholte, H. R. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. Journal of translational medicine 8, 93 (2010).
21.        Castro-Marrero, J. et al. Could mitochondrial dysfunction be a differentiating marker between Chronic Fatigue Syndrome and Fibromyalgia? Antioxidants & redox signaling (2013).doi:10.1089/ars.2013.5346
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24.        Shungu, D. C. et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR in biomedicine 25, 1073–87 (2012).
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3 comments:

  1. I like your blog, however there is no working RSS or Atom feed for your blog. The link that sasy "Subscribe to: Posts (Atom)" does not lead to a working feed

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  2. I have chronic fatigue syndrome. I feel the line of the research goes a long way to explaining the symptoms I have had. What I want most of all is to recover. Do people recover? Does the mitochondrial dysfunction reverse or is it permanent?

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    1. I certainly can't answer these questions definitively. There are some small reports in the scientific literature of people fully recovering in response to treatments, as well as some anecdotal stuff online. The bulk of people with CFS people probably improve at least a bit, whilst some more severe cases probably don't. This doesn't mean you can't improve significantly, its just that the condition isn't fully understood yet in the scientific community, even less so at the clinical level.

      CFS itself may consist of many different subgroups requiring different treatment. Mitochondrial dysfunction may occur for different reasons in each person. There is no evidence I am aware to suggest it is permanent, but it is far from being understood. Some aspects of mitochondrial dysfunction may be easy to fix however, like cofactor insufficiency. Mitochondrial membranes can be replace with NT factor. Toxin-adducts may need to be removed. Redox restored. Getting control of immune dysregulation and inflammation is likely crucial to most which means considering other things such as the gut and infections. There is a lot more research required to figure all this out.

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