“A Cellular Chronic Fatigue” -Dysregulated Mitochondrial Respiratory Function, Metabolic and Signalling Pathways in ME/CFS...,'21,Missailidis (thesis)

Discussion in 'ME/CFS research' started by Dolphin, Aug 21, 2021.

Tags:
  1. Dolphin

    Dolphin Senior Member (Voting Rights)

    Messages:
    5,650
    via Dr. Marc-Alexander Fluks


    Source: La Trobe University
    Date: March 29, 2021
    URL:
    https://opal.latrobe.edu.au/article...ood_Cell-Based_Biomarkers_of_Disease/15153465


    'A Cellular Chronic Fatigue'-dysregulated mitochondrial respiratory
    function, metabolic and signalling pathways in ME/CFS and the
    identification of blood cell-based biomarkers of disease
    -------------------------------------------------------------------
    Daniel Missailidis
    - La Trobe University
    - School of Life Sciences, Department of Physiology, Anatomy and
    Microbiology, Discipline of Microbiology, College of Science,
    Health and Engineering, La Trobe University, Victoria, Australia


    Abstract

    The lack of objective, timely, and accurate diagnostic criteria or
    biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
    (ME/CFS) can leave patients for long periods without a clear diagnosis.
    Treatment is often based on individual trial and error due to the lack
    of mechanistic understanding of the disease. It is therefore paramount
    that fundamental molecular explanations for the underlying
    pathophysiology of ME/CFS are pursued, as these could contribute towards
    the development of reliable, faster diagnostics and rational, effective
    treatments.

    To address these issues, this PhD project has focused on using stably
    proliferative and metabolically active cell lines(lymphoblasts)created
    from ME/CFS patient blood (for the first time) to investigate
    mitochondrial function, related metabolic or signalling pathways, and
    potential diagnostic biomarkers. The results show that in ME/CFS
    lymphoblasts, there is an isolated Complex Vinefficiency in ATP
    synthesis at the final step in mitochondrial oxidative phosphorylation.
    This is accompanied by multiple homeostatic compensations including
    increased respiratory capacity, elevated expression of a diverse array
    of mitochondrial proteins, elevated Target of Rapamycin Complex I
    (TORC1) activity, and evidence suggesting dysregulated substrate
    provision towards the TCA cycle and oxidative phosphorylation.

    Whole-cell proteomics and transcriptomics suggested that in ME/CFS
    lymphoblasts there is an increased use of alternatives to glycolysis in
    provisioning the mitochondria with oxidisable substrate. This may
    represent a homeostatic compensation for the respiratory inefficiency by
    Complex V.Together, these compensatory changes appear to be sufficient
    to meet the normal needs of active metabolism despite the inefficiency
    of ATP synthesis by Complex V. However, this may leave the cells less
    able to respond to further acute increases in ATP demand despite the
    elevated respiratory capacity, since the signalling and metabolic
    pathways involved are already chronically upregulated.

    If this 'cellular chronic fatigue' is present in other cell types, it
    may contribute to the unexplained fatigue experienced by ME/CFS
    patients. This is suggested bythe fact that all of the mitochondrial
    abnormalities observed were correlated with the severity of patient
    symptoms. It was also found that multiple observed abnormalities
    constituted promising biomarkers, each of them able to distinguish
    ME/CFS patient and control samples with high reliability, while 100%
    discriminatory accuracy became possible when using the best combinations
    of variables available. This project has therefore made significant
    strides in the mechanistic understanding of ME/CFS and has highlighted
    promising candidate diagnostic biomarkers.
     
  2. Wonko

    Wonko Senior Member (Voting Rights)

    Messages:
    6,812
    Location:
    UK
    Is this another 'over enthusiastic' thing coming out of Australia?

    Looks good on the face of it, given I know little of such things, but so much ME stuff coming out of Australian universities is.....over hyped.
     
    Louie41, alktipping, sebaaa and 3 others like this.
  3. Hutan

    Hutan Moderator Staff Member

    Messages:
    28,883
    Location:
    Aotearoa New Zealand
    No, most of the over-hyped studies come out of Griffiths University. Daniel is a member here and has taken the time to engage with us. He is part of a team that has done interesting work on mitochondrial dysfunction. We have looked at some of their published studies.

    (click on the missailidis tab above for some relevant threads)
     
    Amw66, oldtimer, Campanula and 25 others like this.
  4. Kalliope

    Kalliope Senior Member (Voting Rights)

    Messages:
    6,526
    Location:
    Norway
    This was submitted as a thesis in 2016. Wonder why it's uploaded just now?
     
    Louie41, Lidia, alktipping and 3 others like this.
  5. dave30th

    dave30th Senior Member (Voting Rights)

    Messages:
    2,406
    was it published anywhere?
     
    Louie41 and Kalliope like this.
  6. Midnattsol

    Midnattsol Moderator Staff Member

    Messages:
    3,741
    What dave30 said. My thesis (and others who like me have worked with data to be published) are not available in the public domain.
     
  7. DMissa

    DMissa Senior Member (Voting Rights)

    Messages:
    137
    Location:
    Australia
    Hello people, a few answers, comments and a general statement I've wanted to make which is probably best placed in this thread.

    Hi there, thanks so much for your input. I am the author of the thesis posted in this thread. I very much strive to phrase or interpret things cautiously and to reflect upon my own results with the appropriate scientific skepticism, so if any of the phrasing of the thesis abstract in particular appeared to be "making a big deal of things" it may just be an (annoying) writing decision made at the time to make the thesis clearly "novel" to any bureaucratic/non-scientist hands it may have had to pass through during processing (PhD theses have to contain novel outcomes to be valid). I avoid doing so in publications. I hope that I was still pretty conservative with the phrasing here, but if anything there would come across as "over-enthused" I apologise - it certainly isn't in my nature as a person or scientist nor my intention. I've had my own personal experience with misdiagnosed and untreated disability + pain, so I truly mean it when I say that deep empathy and genuine outcomes are my motivators. I hope that this attitude is reflected in the science itself (and the writing in the prior publications), but I leave you to be the judge.

    My PhD ran from 2017-2021 (submitted during 2021). In 2016 I undertook my Honours year, perhaps that is the source of any potential confusion or incorrect year wherever it may have been listed.

    Technically no, but it is largely a compilation of our lab's previous ME/CFS papers, amended with my improved knowledge, experience and some newly analysed data at the time of writing.

    And now the general statement I alluded to; I'll be taking an indefinite absence from s4me from the time of posting this. I haven't been active for a long time anyway, but I thought I'd explain my reasoning. I believe very strongly in the value of open, unbiased, critical discourse. Whenever work I am involved in is posted here, even just the possibility that I may read the comments or engage in the thread could affect the discussion (whether by s4me members being more reserved with criticism where they might not be otherwise, or due to the effects of my own comments). In the past I have strived to comment in a neutral manner but this is still likely to bias the discussion (in retrospect, I somewhat regret my involvement due to this possibility). But I would still like to engage with the community and be available, so while I sign off here on s4me I will note that I would love to continue answering questions or even just have a chat over email. Please contact me directly by email if you wish to do so! I think that this is a good compromise which will allow unbiased critical discussion to flourish here on s4me while still allowing individuals to contact me privately if they wish.

    Wishing everybody all the best, always. :)
     
    Last edited: Feb 25, 2022
    Robert 1973, Andy, Michelle and 17 others like this.

Share This Page