How does Mitochondria Dysfunction factor into the theories that you and Dr. Yasko have regarding the Methylation Cycle?
In my hypothesis (the Glutathione Depletion--Methylation Cycle Block hypothesis) glutathione becomes depleted (which is observed in lab testing), and this leads to lack of protection for B12 (this is based on the current biochemical picture that glutathione normally reacts with B12 at an intermediate stage in its metaboism in the cells, producing glutathionylcobalamin and protecting the B12).
The B12 is then hijacked by toxins (B12 is known to be very chemically reactive, and toxins build up when glutathione is depleted).
This shuts down methionine synthase in the methylation cycle (This is based on lab measurements of SAMe and SAH in the methylation cycle, and is consistent with the known requirement of methylcobalamin as a coenzyme for methionine synthase.).
The folates then leak out of the cells via the "methyl trap" mechanism (This is a known mechanism. The folates in the cell are converted to 5-methyl THF, and since it cannot be used by methionine synthase, it builds up. Since this folate does not have a glutamate tail, it is able to leak out of the cells into the blood plasma. Over time, this lowers the total folate in the cells).
A vicious circle forms between glutathione depletion and the partial block of the methylation cycle (This is observed in lab testing, but we do not yet understand the exact mechanism). This is the backdrop for everything else in CFS., because it brings down the immune system, the detox system, and several aspects of the endocrine system, as well as the mitochondria (This is based on the known biochemistry of the sulfur metabolism as well as observations that these systems are dysfunctional in CFS).
In the mitochondria, depletion of glutathione allows the levels of reactive oxygen species to rise (Oxidative stress is perhaps the best known biochemical feature of CFS, based on many measurements). These are produced as a normal part of the oxidation of foods to make ATP, but without sufficient glutathione, they increase in concentration.
The reactive oxygen species react with enzymes in the Krebs cycle and the respiratory chain (These are known reactions, involving the enzymes that incorporate an iron-sulfur complex), within the mitochondria, de-activating them. Peroxynitrite is one of the reactive species that forms, (and this is one place where my hypothesis shares part of Marty Pall's NO-ONOO model. The reaction with aconitase in the Krebs cycle is supported by measurements of Krebs metabolites in urine organic acids tests on many PWCs).
This lowers the rate of production of ATP, which impacts the skeletal muscle (causing the observed physical fatigue), the heart muscle (causing the observed diastolic dysfunction), and the brain and nervous system (contributing to the brain-related symptoms of CFS). (Myhill et al. have published a paper reporting testing that shows low ATP in CFS, and ATP is known to power the muscles and the neurons, as well as many reactions in other types of cells).
Over time, other factors that result from the depletion of glutathione also come into play in causing more dysfunction of the mitochondria (This is based on the known functions of glutathione, including functions involving the detox system and the immune system). These include buildup of toxins, viruses, lactic acid and calcium, and loss of magnesium (Mito dysfunction causes buildup of lactic acid from the glycolysis chain. Disruption of the Ca and Mg levels results from insufficient ATP to power the membrane ion pumps properly). So while the first cause of mito dysfunction in CFS is glutathione depletion, these other factors show up in the Acumen Lab tests that Dr. John McLaren Howard carries out on people who have had CFS for some time. One of the toxins that has been showing up in the women particularly is a chemical that comes from hair dye.
In my hypothesis, the way to address these issues is to get the methylation cycle operating normally again. When this is done (and we have used the socalled "Simplified Treatment Approach," which was extracted from the full Yasko treatment program), we have found that glutathione comes up automatically. Over time, this should clear out the other problems in the mitochondria. Patients in our clinical study of this treatment reported a significant increase in energy, which suggests that their mitochondria were performing better. We also measured a significant increase in plasma glutathione, whiich I believe is consistent with the hypothesis (This is based on the clinical study carried out by Dr. Neil Nathan and myself, reported at the IACFS/ME conference in early 2009).
I think that Dr. Yasko's picture of the mechanisms behind mito dysfunction is similar to the one I have outlined above, though she also emphasizes supplementing some of the things that become depleted in the mitochondria as a result of the methylation cycle block. Dr. Yasko's emphasis is on treatment, while mine is on trying to understand the mechanisms, though I am also, of course, interested in treatment, especially treatment that is not too complex or expensive, so that it is feasible for use by most PWCs.