Monday, October 23, 2023

Credo

There was a line by karl in a  comment to my last post which triggered a summary of my current thinking about life and signals. A lot of this covers ideas I've had for a long time but not blogged about and, as I can never be sure a post will write itself, here is a thought dump to lay it out without any detail or references. As karl said:

"My hunch is the ROS signal is more primitive than insulin itself?"

In response:

Hi karl,

Superoxide is crucial to bacterial (and archaeal) growth, division and death.

Mitochondria retain this signalling system based on a bacterial ~200mV membrane potential.

The cell surface membrane (archaeal derived) has relinquished its 200mV potential to mitochondria.

Cell surface signalling still uses superoxide but this is now NOX controlled.

It provides the same signal as mitochondrial superoxide but has differing cues and locations.

Larger multicellular organisms use a pancreas to condense/combine these ROS signals in to a redox signal carried by a pair of -S-S- double bonds (ox stress marker, think of as a glutathione G-S-S-G mimetic) between two short peptides to encode and transmit an assessment of whole body redox status from the circulation, via the circulation.

Individual cells respond/resist this signal by making superoxide in response to it then modulate it using their own locally derived NOX/RET superoxide signals.

There is no need for it to be the insulin/insulin receptor combination that carries this signal, any -S-S- di-peptide and an appropriate receptor will do. Most metazoans use insulin/insulin receptor but plants, protozoa and yeasts made different choices but they all do the same job.

These assorted signalling systems cross react across all eukaryotes because the underlying ROS signal is fundamental.

Mitochondrial (bacterial style) ROS from RET in ETC -> mitochondrial division (biogenesis) = Good™.

Cell surface (eukaryote invented) NOX ROS -> cellular division -> tissue growth (+ cancer) = potentially Bad™.

Aside: Bad™ stolen from @KetoCarnivore on X/Twitter. End aside.

That LUCA, even before her division in to bacteria/archaea and while living in an anoxic hydrothermal vent, had a globin ancestor to bind O2, an SOD ancestor (based on Fe) to convert superoxide to H2O2 and a catalase to detoxify H2O2 suggests to me that O2 was available, rare/precious and used as a signal (by accepting an electron -> superoxide) of "membrane" potential (ie opportunity to grow, ie superoxide signal) which had to be processed and terminated at a time even before cell membranes were genetically specified.

Obviously catalase derived O2 would be re-stored by the globin for re-use. LUCA (in a deep anoxic ocean) would have derived a meagre supply of precious O2 from the radiolysis of water, a process still used by deep earth-crust bacteria living at a mile below the nearest O2 supply at the earth's surface, even today.

This is my most simplistic view. Without it I can't understand mice becoming obese eating an "high fat" diet. With it I’m spared the deeper intricacies of intermediary metabolism, a complex system if ever there was one.

Peter

7 comments:

  1. Did you finish the bottle🍷? 🥰

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  2. Hi Cap'n, That will probably be on the post about running the membrane bound hydrogenase of pyrococcus furiosus in reverse, the way LUCA did, and squeezing an electron on to an O2. Maybe...

    Hope you're well.

    Peter

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  3. Hi Peter, Yes, all good with me, my 4 kids, and the 8 g'kids tks! However, I'm also just watching the world fall apart but, after 30 years, and aged 72, I finally made it to a single (9.4) golf handicapper (...yaaaawn!). So, something must be right in the world. Maybe being non-vaxxed has helped? I've now also become a part-time greenkeeper in my dotage, mowing the greens at dawn, and chopping down the forest (we/WGC are allowed to). It keeps me fit. I have also fully ditched my car and now (18 months), and cycle everywhere. My main struggle today is following your mitochondrial reductions. I really wish I could keep up, but I do at least try. Anyway, thank you for pushing me toward Nick Lane's books. I just luv 'em. Maybe it's time you wrote a book?

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  4. Sounds excellent Cap'n, congrats on the handicap!

    P

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  5. Basti, yep, that sounds pretty close to how I see it.

    More time needed to explain further

    P

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  6. Awesome blog! Very helpful and understanding article with good knowledge sharing.

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  7. The link to Nick Lanes paper - and time thinking while hiking through the woods has me wondering further about the nuclear vs MT match.

    In one of his books, Nick Lane talked about the birth of eukaryote being a singular event - an event that fundamentally changed life that was before limited by the surface-area to volume ratio of earlier cells. ( OT: Surface-area/volume ratios also explain MANY other key effects in the world - why sneeze droplets evaporate in the order of a second, why the surface area of consumed toxins in more important than volume, why vertical air temperature gradients go to zero in misty weather (which changes sound propagation) - etc etc).

    This birth of eukaryote gave us MT - and larger more complex cells. But for it to work, there has to be some level of coordination between Nuclear and MT DNA. This jump to coordination of DNA is key - without it - early eukaryote cells would like die out. How on earth did it happen?

    Having local DNA in the MT seems to matter in the speed of response - a control loop issue. The question is just how the Nuclear to MT control loop works? Bidirectional signaling? ROS could be the signal from the MT to the nucleus that it was running over throttled? Wonder if there is some nucleus system to react to ROS levels?

    There is good evidence from hybrids that the matching of Nucleus and MT (they call this Mitochondrial–nuclear epistasis) is quite sensitive - if the match is off, one effect is sterile offspring - and that effect seems to have a sex preference (is it the male gametes that run a sort of asexual gauntlet of selection?). Why is it that hybrids function in so many other ways - but are sterile is a question that might help understand the interaction. The mtDNA in sperm seems to be missing - so how does the MT even work?
    https://www.nature.com/articles/s41588-023-01505-9
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904680/

    https://sci-hub.se/10.1016/j.arr.2010.06.003

    Any way - no end of things to puzzle over.

    Drifting seriously OT:

    200mv is a voltage that is of interest in electronics. It is just high enough to run semiconductors:
    https://pubs.aip.org/avs/jva/article-abstract/24/3/763/245804/Very-low-voltage-operation-capability-of?redirectedFrom=fulltext

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