Version 1
: Received: 3 September 2019 / Approved: 4 September 2019 / Online: 4 September 2019 (13:29:14 CEST)
Version 2
: Received: 26 January 2020 / Approved: 27 January 2020 / Online: 27 January 2020 (10:09:08 CET)
Version 3
: Received: 2 February 2020 / Approved: 3 February 2020 / Online: 3 February 2020 (09:34:29 CET)
Missailidis, D.; Annesley, S.J.; Allan, C.Y.; Sanislav, O.; Lidbury, B.A.; Lewis, D.P.; Fisher, P.R. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int. J. Mol. Sci.2020, 21, 1074.
Missailidis, D.; Annesley, S.J.; Allan, C.Y.; Sanislav, O.; Lidbury, B.A.; Lewis, D.P.; Fisher, P.R. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int. J. Mol. Sci. 2020, 21, 1074.
Missailidis, D.; Annesley, S.J.; Allan, C.Y.; Sanislav, O.; Lidbury, B.A.; Lewis, D.P.; Fisher, P.R. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int. J. Mol. Sci.2020, 21, 1074.
Missailidis, D.; Annesley, S.J.; Allan, C.Y.; Sanislav, O.; Lidbury, B.A.; Lewis, D.P.; Fisher, P.R. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int. J. Mol. Sci. 2020, 21, 1074.
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic condition characterized by fatigue that is unaided by rest and by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”). There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolising patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by an elevation of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signalling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.
Biology and Life Sciences, Cell and Developmental Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
5 September 2019
Commenter:
Bea Blakely
The commenter has declared there is no conflict of interests.
Comment:
Thank you for a very interesting paper. I particularly appreciate that you are looking at how your findings link to clinical relevance - something that's all too often forgotten.
May I, however, suggest an alternative to your opening sentence, if too late for this paper then for future ones? The sentence contains a misconception that appears to have become "truth" by force of being cited by reflex in almost every piece of writing about ME, creating a sort of self-reinforcing feedback loop. I'm referring to the phrase : "characterized by fatigue that is unaided by rest". This is problematic for two reasons.
One, fatigue is not a specific characteristic of ME. PEM is. So there is actually no need to mention fatigue in the opening sentence at all. If you do wish to refer to it, it would be more accurate to use the expression "profound exhaustion", or similar, instead. It is at least less likely to (mis)lead the mind towards the notion of 'sleepy-tiredness'.
Two, and more importantly, fatigue/profound exhaustion is, in fact, alleviated by rest. It must be, or else patients would experience the same level of fatigue/profound exhaustion whether they are in PEM after overexertion or not, which is not the case when they can rest enough (which isn't always possible of course). The real abnormality in ME is not that rest doesn't help, it does, but that ME patients need much more rest than healthy people to achieve a reduction in fatigue/profound exhaustion.
Here are two alternative suggestions for your opening sentence:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood condition characterized by an abnormal exacerbation of symptoms after exertion (post-exertional malaise or “PEM”).
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood condition characterized by an abnormal exacerbation of symptoms after exertion (post-exertional malaise or “PEM”) and by profound exhaustion disproportionate to the triggering activity and which is not fully alleviated by normal amounts of rest.
The commenter has declared there is no conflict of interests.
Comment:
This 1st version of this manuscript contains an error which we would like to alert readers to:
During revision of the paper, we discovered an error in the spreadsheet formula calculating the mitochondrial membrane potential. This is calculated by dividing one quantity by another. However the original formular had been entered into the spreadsheet the wrong way round so that instead of "a" being divided by "b", "b" was divided by "a".
The result was that instead of the mitochondrial membrane potential being higher in ME/CFS lymphoblasts it was actually lower. The error has been corrected in a revised version of the article which has been submitted to Preprints.
The authors would like to apologize for this embarrassing calculation error.
Best regards to all readers
Paul Fisher on behalf of all authors.
,
,
,
Commenter: Bea Blakely
The commenter has declared there is no conflict of interests.
May I, however, suggest an alternative to your opening sentence, if too late for this paper then for future ones? The sentence contains a misconception that appears to have become "truth" by force of being cited by reflex in almost every piece of writing about ME, creating a sort of self-reinforcing feedback loop. I'm referring to the phrase : "characterized by fatigue that is unaided by rest". This is problematic for two reasons.
One, fatigue is not a specific characteristic of ME. PEM is. So there is actually no need to mention fatigue in the opening sentence at all. If you do wish to refer to it, it would be more accurate to use the expression "profound exhaustion", or similar, instead. It is at least less likely to (mis)lead the mind towards the notion of 'sleepy-tiredness'.
Two, and more importantly, fatigue/profound exhaustion is, in fact, alleviated by rest. It must be, or else patients would experience the same level of fatigue/profound exhaustion whether they are in PEM after overexertion or not, which is not the case when they can rest enough (which isn't always possible of course). The real abnormality in ME is not that rest doesn't help, it does, but that ME patients need much more rest than healthy people to achieve a reduction in fatigue/profound exhaustion.
Here are two alternative suggestions for your opening sentence:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood condition characterized by an abnormal exacerbation of symptoms after exertion (post-exertional malaise or “PEM”).
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood condition characterized by an abnormal exacerbation of symptoms after exertion (post-exertional malaise or “PEM”) and by profound exhaustion disproportionate to the triggering activity and which is not fully alleviated by normal amounts of rest.
Commenter:
The commenter has declared there is no conflict of interests.
During revision of the paper, we discovered an error in the spreadsheet formula calculating the mitochondrial membrane potential. This is calculated by dividing one quantity by another. However the original formular had been entered into the spreadsheet the wrong way round so that instead of "a" being divided by "b", "b" was divided by "a".
The result was that instead of the mitochondrial membrane potential being higher in ME/CFS lymphoblasts it was actually lower. The error has been corrected in a revised version of the article which has been submitted to Preprints.
The authors would like to apologize for this embarrassing calculation error.
Best regards to all readers
Paul Fisher on behalf of all authors.