Mitochondrial Depletion Could Underlie the Energy Problems in Chronic Fatigue Syndrome, comment by Cort Johnson, May 26, 2015
Very, very few chronic fatigue syndrome studies have emerged from Germany, but the last two have been good ones. The one before this was the first to find evidence of EBV activation in ME/CFS, in years.
This one – a model exploring mitochondrial dynamics – may help explain what’s causing the post-exertional problems, published in the Biophysical Chemistry journal, this study extended a well-known metabolic model explaining what happens to the mitochondria in the skeletal muscles during exercise. The authors enhanced it by adding some processes to it (lactate accumulations / purine degradation) known to occur in the mitochondria.
In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Nicor Lengert, Barbara Drossel Institute for Condensed Matter Physics, Technische Universität. Biophysical Chemistry 202 (2015) 21–31
The Study
The model covers two parts of the inner mitochondria – the cytosolic space and the mitochrondrial matrix. It does not cover interactions between the mitochondrial membrane and the rest of the mitochondria.
The model was rather….complex.
The production of the model was sparked by a number of findings (reduced ATP production and peak oxygen uptake) suggesting problems with aerobic (oxygen related) energy production, were present in chronic fatigue syndrome. Findings of increased acidification, reduced anaerobic threshold and prolonged pH recovery times suggested that anaerobic respiration – a less efficient and more toxic form of energy production – was attempting to compensate for a broken aerobic energy production system.
They noted that several factors that could affect mitochondrial activity. They included possible “mitochondrial deletions”, Epstein-Barr virus induced alterations of mitochondrial gene transcription, pro-inflammatory cytokines and increased levels of oxidative stress.
They ran two iterations of the model; one representing the reactions in the mitochondria occurring in healthy controls, and one representing a person with probably severe ME/CFS, for whom mitochondrial capacity was reduced by about a third. Then they examined what happened during three exercise scenarios: 30 seconds of intensive exercise, an hour of moderate exercise and an hour of moderate exercise spread across two days. Then they looked to see if the models fit what the studies suggest is happening in ME/CFS.
It turns out that they did.
Results
ATP reaches critically low concentrations during high intensity exercise in CFS simulations and the acidification in muscle tissue increases compared to control simulations. [Authors]
Several studies suggest that the rates of ATP production/oxidative phosphorylation (mitochondrial capacity) are about 65% of normal in ME/CFS. This model suggests reduced mitochondrial capacity could be causing the ATP problems and the increased acidosis and lactate accumulations found in several studies. (The increased acidosis is the problem, lactate is not. Lactate is produced to protect the cell from acidification.)
Healthy people are able to maintain an ATP level during exercise that protects their mitochondria. The models suggested, however, that the minimum ATP levels maintained in ME/CFS patients during exercise, may be significantly lower – low enough perhaps to induce cell death. This finding was buttressed by one of Sarah Myhill’s studies, which found greatly increased levels of a factor (cell-free DNA) that’s associated with increased cell death.
When the mitochondrial capacity of a cell is exhausted; i.e. when ATP demand outstrips supply the cell copes with this by digging into its reserves. Converting two ADP molecules to one ATP and one AMP molecule, frees up some energy (ATP), but does two negative things as well. First, it reduces the total adenine pool in the cell (adenine triphospate (ATP) and diphosphate (ADP)) and second it increases levels of inosine, hypoxanthine and finally uric acid.
The model suggested that the healthy controls in the model were able to exercise without purine nucleotide loss while the people with reduced mitochondrial dysfunction suffered from significant losses of purine nucleotides.
Acidosis Plays Key Role
Anaerobic respiration greatly increases the rate of acidosis. Acidification is produced by the breakdown (hydrolysis) of ATP and is related, if I have it right, to increased rates of cell damage and subsequent purine nucleotide loss. The model suggested that the increased acidosis in the “ME/CFS patients” increases lactate accumulations and lactate efflux from the cell by 10-15%. The situation in ME/CFS might be worse, however, than the model with its forty percent reduction in mitochondrial production suggested. The rates of acidosis and lactate accumulations found in ME/CFS studies were significantly higher than those produced by the model.
Prolonged Recovery Periods
The reduction in the adenine pool means the cell will need time in the post-exercise period to get back to normal. After prolonged bouts of intense exercise even professional athletes need 72 hours to replenish the adenine pools in their muscle cells. But what would short periods of exercise to please with reduce exercise capacity? The model predicted it would take 3-5 times longer for the ATP levels in the muscles of ME/CFS patients to return to normal after exercise than for healthy controls. The model predicted that short (30 seconds), intense exercise periods would be easier for “ME/CFS patients” to recover from.
The model predicted it would take 49 hours for ATP levels in the muscles to return to normal after a longer (30 minutes) but more moderate period of exercise. It would take 32 hours for the ATP levels in the muscles of ME/CFS patients to return to normal after short but intense (30 secs.) periods of exercise. Adding another exercise bout before recovery could occur would add substantially more time to the recovery period.
The findings provide another possible reason (ATP depletion) for the post-exertional malaise seen in ME/CFS. It could also explain why some people with ME/CFS cannot reproduce their levels of energy on the second day of a bicycle exercise test.
The model did not account for the possibility of increased cell death during exercise – something the researchers thought likely – that would extend recovery times further. Other factors, such as sympathetic nervous system and immune dysregulation and increased oxidative stress, not included in the model, may also come into play.
Recovery Reversal
..the model…. demonstrates that long moderate exercises are more exhaustive than short intensive exercises contrary to the results for healthy controls. Authors
The model suggested that mitochondrial depletion results in more difficulty with longer bouts of moderate exercise, than with shorter bouts of intense exercise. This pattern was opposite to that found in the controls. Healthy controls recover more quickly from longer moderate bouts of exercise (4.5 hours) than short, intense bouts of exercise (10.3 hours). The altered scenario fits well with recommendations by exercise physiologists for ME/CFS suggesting that exercise periods be short and interspersed with rest perios
Two Subsets?
Studies of mitochondrial respiration in the neutrophils in ME/CFS suggested two groups of mitochondrial deficient ME/CFS patients may be present. One group compensates for the mitochondrial deficiency by upregulating glycolysis and the other by increasing purine nucleotide degradation. This model in this paper suggests both are possible.
Treatment
The authors suggested that D-Ribose could help in the short term but worried about its “rapid glycation of proteins” – something they said was associated with some neurodegenerative diseases. They suggested measuring mitochondrial respiration co-factors (ubiquinol (CoQ10), NAD, L-carnitine and others) and supporting it with supplements.
Wrap Up
The new model produced in this study extends a less sophisticated model of mitochondrial metabolism. That fact that it was produced in response to findings in ME/CFS, is in itself interesting, and suggests how unusual the findings in ME/CFS exercise studies are. It should be emphasized that this is a model, and therefore does not necessarily demonstrate what’s happening in ME/CFS.
The model indicates that reduced mitochondrial production could, however, help explain the exercise findings, and post exertional malaise studies indicate it is present in ME/CFS. It buttresses the idea, emerging more strongly in ME/CFS in recent years, that the mitochondria may play an important role.
It did this by showing how, when put under load, reduced mitochondrial capacity feeds on components of the cells to make energy. This works in the short term, but in the longer term depletes the cells of vital energy making factors. This long term depletion – lasting for at least a day, but possibly much longer – could help explain the post-exertional malaise and difficulty reproducing energy production, in the second day of a two day exercise test.
It indicated that shorter periods of exercise – even if they are more intense – should be easier to recover from, than longer periods of more moderate exercise. Because the model failed to predict the very high levels of lactate and acid production found in some ME/CFS studies, it may be understating the depth of the mitochondrial depletion found. It does not say anything about what is causing the possible depletion of mitochondrial capacity.
The authors suggested the appropriate supplementation (CoQ10, NAD, L-carnitine) may be helpful.
