|The mitochondrion (click to enlarge)|
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; while 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 while 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; while a couple of other studies failed to find any changes in blood levels 31,32. Low Co-Q10 levels in PBMCs 21 and serum have been reported in CFS 33 and correlate with illness severity 34. Another bioenergetic factor, magnesium, has also been reported to be deficient in CFS 33,35. Supplementation with carnitine 36,37, NADH 38–40 or D-ribose 41,42 had beneficial effects in several studies. Changes to the make-up of the mitochondrial membrane have also been implicated in CFS 43,44, and treatment aimed at restoring membrane integrity (lipid replacement therapy, LRT) significantly decreased fatigue in a small study on CFS patients 44.
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.
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