Hi, Cort.
I've now read the full Vermeulen et al. paper. Here are some comments:
1. In their study, the cells were stored with DMSO (dimethyl sulfoxide). This is a very good antioxidant, and is able to cross cell membranes and enter cells readily. It very likely eliminated the oxidative stress that the cells were under when they were in the bodies of the PWCs. This is a very important point, since oxidative stress is well established in CFS, as the authors noted, and there are mechanisms built into the mitochondria to limit the rates of flow through both the Krebs cycle and the respiratory chain in response to oxidative stress. It has been suggested that this is a protective mechanism to limit the damage that would occur if these rates were not limited. There is published literature in support of this mechanism. As you may recall, in the GD-MCB hypothesis, I have suggested that depletion of glutathione, which is intrinsic in oxidative stress, is a major factor leading to mito dysfunction. DMSO could have compensated for low glutathione with the sample handling used in the Vermeulen study, rendering its results for the activities of the respiratory chain enzymes spurious.
2. The level of creatine kinase in the blood plasma was used as a measure of oxidative phosphorylation, based on a study involving a genetic mitochondrial disease. The creatine kinase level in the plasma is actually a measure of the rate of cell death. The relationship between the rate of oxidative phosphorylation and the rate of cell death may be quite different in the mito dysfunction of CFS compared with the genetic mito disease chronic external ophthalmoplegia. This is certainly not a very direct measure of the rate of oxidative phosphorylation. The methods used by Dr. John McLaren Howard of Acumen Lab in the UK are more direct measures of the processes occurring in the mitochondria. As a related point, the creatine system in CFS is not operating normally, since the synthesis of creatine is normally the major user of methylation in the body, and we have found by lab testing that there is a partial block in the methylation cycle, leading to a methylation deficit. Based on urine creatinine measurements (which are usually low in PWCs), it seems likely that the creatine synthesis is low, which would be consistent with the observed methylation deficit. In view of this, it may well be that the expression of creatine kinase, which is the enzyme that reacts creatine with phosphate, is abnormal in CFS as well.
3. I agree with WillowJ that the parameters measured in the Vermeulen et al. study would not give a complete picture of mito function, even if the issues discussed above were not present. An example of another aspect that can be observed readily is the levels of the Krebs cycle metabolites in the urine, as seen in urine organic acids testing, such as with the Genova Diagnostics Metabolic Analysis Profile (MAP). I have seen results of this panel from a large number of PWCs over the past several years, and it is unusual to find these levels close to their midranges. When glutathione is seriously depleted, there is a partial block at aconitase in the Krebs cycle, and this causes the citrate level to be high relative to those that follow it, which are downstream of the partial block at aconitase. This is a feature I have seen many times. In some other cases, I have seen very low levels for all the Krebs metabolites, and these people have very serious mito dysfunction and very low energy levels. This is usually accompanied either by low plasma amino acids levels or a deficit in vitamin B6, or both, which cause the rates of anaplerosis to be low. (Anaplerosis or "filling up" is the process by which the amino acids normally replenish the metabolites of the Krebs cycle.)
3. The alternate explanation for the insufficient energy production in CFS that was offered by Vermeulen et al. is not tenable in the light of the (unfortunately unpublished) results of pulse oximetry during breath holding and IVRT measurement during application of additional oxygen by mask that Dr. Cheney has observed. Here is a description of what he has reported:
When he attaches a pulse oximeter to the finger of a PWC and asks them to hold their breath for 30 seconds, he finds that they start with a % oxygen saturation in their arterial blood that is in the normal range (95-98%), and then he finds that it does not drop very much or at all during the breath holding, compared to normal, healthy people, in which it does drop. This indicates that sufficient oxygen is being carried by the blood, but that the cells are not utilizing it.
When he sets up to monitor the IVRT (isovolumetric relaxation time) on the echocardiograph, and then gives supplementary oxygen by mask to a person with CFS, he finds that the IVRT increases, as compared with normal, healthy people, in which it does not increase. The IVRT is a measure of diastolic dysfunction, which is caused by insufficient rate of ATP production by the mitochondria of the heart muscle cells. This indicates that the mitochondria are not being limited by insufficient oxygen. Rather, they are self-limiting due to oxidative stress, and if more oxygen is added, the degree of oxidative stress becomes worse, thus causing more severe mito dysfunction.
About 3 years ago, Dr. Sarah Myhill and I wrote a review of all the published CFS literature we could find pertaining to mitochondrial dysfunction in CFS. We submitted it to the journal Medical Hypotheses, and it was rejected. We then submitted it to the journal Mitochondrion, and it was also rejected. We, of course, believe that the paper has merit, and we may try again in response to papers such as the one by Vermeulen et al. As you can probably imagine, I think it is very unfortunate that it is so difficult to get a review of this type published, when the journals are frequently ready to accept papers involving CFS that contain serious errors (or the ones that imply psychiatric problems in CFS).
Here is the abstract of our draft paper:
Abstract
This paper reviews the evidence that mitochondrial dysfunction is an important part of the pathophysiology of at least a major subset of the population who have chronic fatigue syndrome (CFS). Several types of published supporting evidence are cited, including the following: 1) muscle biopsy and ultrastructural examination; 2) status of mitochondrial nutrients and response to their supplementation; 3) gene expression studies; 4) indicators of abnormal processing of substances that are inputs to the mitochondria; 5) indicators of abnormal production of mitochondrial outputs; 6) apoptosis behavior; 7) heart function; 8) symptoms related to particular organs; and 9) intolerance to fatiguing exercise in CFS. We conclude that there is evidence for mitochondrial dysfunction in cells of the skeletal muscles, the immune system, the brain and the heart in at least substantial subsets of the CFS population. This conclusion points to a need to explain the cause or causes of mitochondrial dysfunction in CFS. It also points to the importance in both CFS research and clinical diagnosis and treatment of performing mitochondrial tests and of measuring levels of ATP. Other features important to the assessment of mitochondrial function should also be measured: nutrient levels, thyroid-related parameters and urine organic acids levels, including the levels of lactic and pyruvic acids, Krebs cycle intermediates, ketones and abnormal fatty acid metabolites.
I will forward the Vermeulen et al. paper to Dr. Howard, and will let you know if he responds. I note that this paper is critical of his work, so I expect that he will have some thoughts to share!

-)
Best regards,
Rich