​ Impairment in Oxidative Phosphorylation oxidative phosphorylation  OXPHOSFrom: 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 | Full Text https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-8-93 The decrease in mitochondrial ATP synthesis in the CFS/ME patients is not caused by a defect in the enzyme complexes catalyzing oxidative phosphorylation, but in another factor. From: Cellular bioenergetics is impaired in patients with chronic fatigue syndrome http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186802 While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study  p≤0.003 . The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand. From: ME/CFS energy metabolism study by Cara Tomas confirms impairment in mito oxidative phosphorylation | Phoenix Rising ME / CFS Forums https://forums.phoenixrising.me/index.php?threads/me-cfs-energy-metabolism-study-by-cara-tomas-confirms-impairment-in-mito-oxidative-phosphorylation.55981/ A study just published in October 2017 by PhD student  and ME/CFS patient  Cara Tomas finds that  mitochondrial oxidative phosphorylation is functioning well under par in ME/CFS patients  at baseline, and that when ME/CFS patients' cells need to generate extra energy in order to cope with increased physiological stress, these cells are  less able to ramp up their energy production  to meet the higher energy demands. So ME/CFS patients' mitochondria are not able to produce enough energy at baseline, and these mitochondria have additional problems when trying to ramp up energy production when higher energy output is required. The published paper by Cara Tomas is here:  Cellular bioenergetics is impaired in patients with chronic fatigue syndrome  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186802 The Tomas study analyzed in vitro the energy metabolism of ME/CFS patient's peripheral blood mononuclear cells  PBMCs , using a commercial laboratory machine  called the  Seahorse XFe96 Analyzer  http://www.agilent.com/en/products/cell-analysis-%28seahorse%29/seahorse-analyzers/seahorse-xfe96-analyzer   which is specially designed to measure cell energy metabolism  thus this study should be reproducible by anyone with such a machine . Interestingly, although oxidative phosphorylation was impaired in ME/CFS, glycolysis in ME/CFS patients' cells was found to be normal. Baseline energy output from anaerobic glycolysis in ME/CFS patients' cells was the same as the healthy control cells; and also the glycolysis stress test  where cells need to ramp up their glycolytic energy production to meet higher energy demands  showed that glycolysis in ME/CFS patients' cells is able to increase energy output when required, just as effectively as healthy control cells. So in ME/CFS, glycolysis is working normally at baseline, and is perfectly able to increase energy output when required. Whereas oxidative phosphorylation was found impaired on both counts. The findings of this study by Tomas broadly match up with the results of the  Myhill, Booth and McLaren-Howard energy metabolism studies  http://forums.phoenixrising.me/index.php?threads/mitochondrial-and-energy-metabolism-dysfunction-in-me-cfs-%E2%80%94-myhill-booth-and-mclaren-howard-papers.47488/ , which found that ME/CFS patients have impaired mitochondria oxidative phosphorylation  as well as impairments in the transport of ADP and ATP in an out of the mitochondria, and other impairments . This Tomas study I think  but am not sure  would also be consistent with  Fluge and Mella's metabolic profiling study  https://insight.jci.org/articles/view/89376 . Fluge and Mella's results suggested an impairment of pyruvate dehydrogenase  PDH , which is an enzyme that couples glycolysis with oxidative phosphorylation. When burning glucose for energy, glucose is first processed by glycolysis  situated outside the mitochondria , and then the energy production process is handed over to the mitochondria, where oxidative phosphorylation completes the job. With an impairment in pyruvate dehydrogenase, there is a partial blockage in this handover, meaning that oxidative phosphorylation does not get a chance to do its job  so from the Fluge and Mella perspective, in ME/CFS oxidative phosphorylation might be fully functional, but does not get a chance to function properly because it is not handed over what it needs . However, oxidative phosphorylation can also burn fats for energy, and fat burning does not rely on glycolysis or pyruvate dehydrogenase, so even if PDH were impaired, it would not alter the fat burning capabilities of oxidative phosphorylation in the mitochondria. So this raises a question mark as to whether in the Tomas study, oxidative phosphorylation was running on the glucose or fat energy production pathway. The Tomas study does talk about adding glucose solution to the cells, which suggests that in this study the energy source oxidative phosphorylation is running on is glucose rather than fats. In which case, the impairment that Tomas found in oxidative phosphorylation could be due to an impairment of pyruvate dehydrogenase, making the Tomas study consistent with the Fluge and Mella paper.A study just published in October 2017 by PhD student  and ME/CFS patient  Cara Tomas finds that  mitochondrial oxidative phosphorylation is functioning well under par in ME/CFS patients  at baseline, and that when ME/CFS patients' cells need to generate extra energy in order to cope with increased physiological stress, these cells are  less able to ramp up their energy production  to meet the higher energy demands. So ME/CFS patients' mitochondria are not able to produce enough energy at baseline, and these mitochondria have additional problems when trying to ramp up energy production when higher energy output is required. The published paper by Cara Tomas is here:  Cellular bioenergetics is impaired in patients with chronic fatigue syndrome  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186802 From: http://jpet.aspetjournals.org/content/jpet/early/2018/08/03/jpet.118.250845.full.pdf Severely reduced or impaired mitochondrial oxidative phosphorylation in ME/CFS patients is highly correlated with significantly increased intracellular lactate levels, even in the recovery phase of a mild exercise where ATP synthesis is extremely low  Vermeulen, et al., 2010 ,  Morris and Maes, 2014 . 

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