1. Less than a week to support David Tuller's work. To donate click here.
    Dismiss Notice
  2. Guest, the 'News in Brief' for the week beginning 19th October 2020 is here.
    Dismiss Notice
  3. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

Video, Emerge Symposium 2019: Dr Paul Fisher, Specific Mitochondrial Respiratory Defects & Compensatory Changes in ME/CFS Patient Cells

Discussion in 'BioMedical ME/CFS Research' started by Andy, Apr 20, 2019.

  1. Andy

    Andy Committee Member & Outreach

    Messages:
    10,818
    Likes Received:
    78,193
    Location:
    Hampshire, UK
  2. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    I finally got around to watching this lecture. I found it absolutely fascinating. I'm no expert, but his findings look really important. And he's continuing the work.

    My lay interpretation is that the mitochondria themselves are normal in quantity, but that one in the series of structures needed to work in sequence to produce ATP (Complex five) is not working efficiently.

    At rest this is overcome by having lots more of the structures in the mitochondrial membrane needed for the process, including more complex V's so enough ATP can be produced to meet energy demands, but if the cell is put under stress and needs to produce more energy, it can't increase its mitochondrial activity to produce more ATP like a normal cell could. It's incredibly complicated, and they don't know why this is happening, but they are continuing researching different aspects trying to figure this out.

    His team used lots of methods including the seahorse analyser and proteomics. He's been a mitochondria expert for a long time, so has a lot of knowledge about what he's doing. Some of the slides during the presentation were hidden because it's not published yet.
     
  3. lansbergen

    lansbergen Senior Member (Voting Rights)

    Messages:
    616
    Likes Received:
    2,246
    I would say, avoid stressers as much as possible.
     
  4. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    Um, why? I can't immediately see any connection with the video...
     
  5. lansbergen

    lansbergen Senior Member (Voting Rights)

    Messages:
    616
    Likes Received:
    2,246
    Complex V problem. Not enough APT production to cope with extra demand.
     
  6. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    Ah, OK. I agree it suggests we need to avoid anything that requires too much energy - or putting it another way, we won't be able to do things that require a lot of energy. I was thinking of it more in terms of physical and cognitive activity which use lots of energy, I guess they are stressors.
     
  7. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

    Messages:
    1,915
    Likes Received:
    13,937
    I’ve listened in as well. So we have upregulated mitochondrial function as a result of cellular stress but cause and effect is still to be determined.

    I was a bit lost as to why he believes the complex 5 to be inefficient....I guess this is not necessarily a permanent feature but may be an effect of something else.

    My read was that there is unlikely to be a simple treatment coming out of this and this could well be something downstream to what causes the cells to be stressed in the first place and perhaps this stress reveals a mitochondrial inefficiency?

    I wonder how the exosomes fit into this? Perhaps these are the things responsible for keeping the cells stressed which in turn makes the mitochondria become inefficient or perhaps some people are genetically inefficient but this is only revealed when the mitochondria are forced to be turned up to the max?

    Of course the exosomes could be downstream of something else as yet unknown?

    Sorry for the speculation ..just thinking out loud.
     
  8. lansbergen

    lansbergen Senior Member (Voting Rights)

    Messages:
    616
    Likes Received:
    2,246
    It is part of the puzzle and I think it is a downstream event.

    Probably

    The pathogen I suspect is transported by exosomes.
     
    Annamaria likes this.
  9. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    We don't know yet that it is a pathogen. Whole pathogens would not, I think be enclosed in exosomes, but bits of their genetic material might be. I just found a paper that explains the relationship between pathogens and exosomes. I'll put it on the exosomes thread so as not to divert this thread.

    Edited to add link.
     
    Last edited: Apr 28, 2019
  10. lansbergen

    lansbergen Senior Member (Voting Rights)

    Messages:
    616
    Likes Received:
    2,246
    They are still fighting over weather the pathogen I suspect has genetic material. Nobody disputs a misfolded protein is part of it.
     
    ukxmrv likes this.
  11. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    3,091
    Likes Received:
    30,807
    After watching this yesterday my question is, would the complex V problem explain why there is a limit to how much we can do?

    I can exceed this limit, indicating that the ability to generate energy is there, but there will be a price to pay in the form of a crash that forces me back to lower activity levels if I keep trying to push and do more. Maybe not immediately but it is unavoidable if the limits keeps being exceeded. So one could say that exertion diminishes the capacity for future exertion (in a way that is not normal).

    Complex V recycles ADP into ATP and I vaguely remember that the idea that this process is impaired has been proposed before.
     
    Annamaria, alktipping, Amw66 and 6 others like this.
  12. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

    Messages:
    1,915
    Likes Received:
    13,937
    Yes that’s how I understand it. We just don’t know enough to say infection has anything to do with anything other than its one of many triggers (at this stage).

    I think the exosome messenger work looks like it has promise. I was interested to read the exosome research in Alzheimer’s and cancer. This to me is very encouraging ...mainly because those illnesses have far more research funding :)
     
  13. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    By definition an pathogen has genetic material, otherwise it wouldn't be able to replicate itself.
    Dictionary definition:
    A pathogen is a bacterium, virus, or other microorganism that can cause disease.
     
  14. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

    Messages:
    1,915
    Likes Received:
    13,937
    I think Myhill (who is a proponent of dysfunction of Mitos) suggested that PEM was a state of depleting ATP and the reserve ADP so that you end up with payback in the form of creation of new AMP/ADP which requires a wait since your body takes a long time to synthesise the ribose element to make new AMP. This seems overly simplistic though.

    My brain is a bit foggy but shouldn’t F&M pyruvate dehydrogenase paper fit with these findings?

    I’m too out of it today but if someone else wants to chip in to suggest how these fit....?
     
  15. lansbergen

    lansbergen Senior Member (Voting Rights)

    Messages:
    616
    Likes Received:
    2,246
    Thats what I thought but many (inclusive nobel prize winners) say this one has not.
     
    Annamaria likes this.
  16. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    Interesting. Can you give a link or indicate who you are talking about and in what context?

    I don't see how something can be described as a pathogen if it can't replicate itself in order be passed on from one person/organism to another and infect it. That requires DNA or RNA (genetic material). Proteins can't replicate themselves.
     
    Annamaria and Andy like this.
  17. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    7,601
    Likes Received:
    78,102
    No, but the idea with prions is that they induce conformational changes in normal versions of the same protein and thereby convert them into more prions. Prions are pathogens.
     
  18. strategist

    strategist Senior Member (Voting Rights)

    Messages:
    3,091
    Likes Received:
    30,807
    What I understood about their findings (not a transcript, just a quick and dirty summary which might contain errors):

    Complex V is operating less efficiently, but basal oxygen consumption is not much different. This indicates that the cells are able to compensate when at rest, but ATP synthesis is about 25% lower in patients. The proton leak is dramatically changed and the non-mitochondrial oxygen consumption is also dramatically changed. Proton leak is dramatically elevated. That's consistent with the upregulation of proteins that import things into the mitochondria. In the lymphoblast cell cultures (what is being studied here) the metabolism is therefore elevated. The mitochondria express more complex I-IV and are trying to make up for the deficiency in complex V, but all that extra capacity can't be used. These measures correlate with disease severity. They also used antibodies and western blots to look at the expression of mitochondrial complex proteins. Everything is consistent with an attempt to cope with an inefficient complex V. They did proteomics and looked for clusters of interacting and proteins related by function and found a cluster related to cell growth and division, one related to assembly of mitochondrial proteins, and one related to mitochondrial metabolism of lipids.
    In the proteins that differ between patients and controls, there is a statistically significant enrichment of mitochondrial proteins. Complex 1 proteins are on average 56% higher in patients.
     
    Last edited: Apr 28, 2019
  19. Trish

    Trish Moderator Staff Member

    Messages:
    26,607
    Likes Received:
    130,546
    Location:
    UK
    Thank you.
     
    MEMarge and adambeyoncelowe like this.
  20. lansbergen

    lansbergen Senior Member (Voting Rights)

    Messages:
    616
    Likes Received:
    2,246
    And pushing through to a point systems can not proper function anymore.
     
    Annamaria, alktipping and MEMarge like this.

Share This Page