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Increased demand for NAD+ relative to ATP drives aerobic glycolysis, 2020, Luengo et al

Discussion in 'Other health news and research' started by Hoopoe, Dec 31, 2020.

  1. Hoopoe

    Hoopoe Senior Member (Voting Rights)

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    5,234
    I wonder whether this anything to do with ME/CFS.

    My thought is that if in ME/CFS some strange metabolic plan is being followed that involves a reduction in pyruvate going into the citric acid cycle, as well as increase in lactate (evidence that this pyruvate is being fermented), then maybe the cells are doing this because they need more NAD+ than usual.

    https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30904-7
     
    Last edited: Dec 31, 2020
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  2. Hoopoe

    Hoopoe Senior Member (Voting Rights)

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    https://www.nature.com/articles/s41392-020-00311-7
     
    Michelle and Kitty like this.
  3. Creekside

    Creekside Senior Member (Voting Rights)

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    My ME symptoms rose dramatically when I took extra tryptophan. Even quickly-digested carbs would make me feel worse 20 minutes later, which is expected as insulin boosts TRP transport into the brain, and is blocked by taking BCAAs. Furthermore, dietary niacin made me feel strongly suicidal. I believe that the lack of dietary niacin was forcing my brain cells to convert excess quinolinic acid to NAD+ to meet demands. Boosting niacin, as an NAD+ precursor, would thus result in QUIN piling up rather than being converted.

    This paper ( https://www.frontiersin.org/articles/10.3389/fimmu.2020.00031/full ) is Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection.

    One bit that caught my attention: "It is possible that prolonged dietary tryptophan excess during a strong immune response may turn out to be an exacerbating factor in certain inflammatory conditions, shifting kynurenine pathway flux from a net positive to an overall negative effect. "
     
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  4. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    NAD+ is (re)generated via the malate-aspartate shuttle and the glycerol-3-phosphate shuttle

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737637/figure/f5/

    The process is reversible and the kinetics depend on the relative concentrations.

    Keeping in mind that cell culture experiments can involve manipulations that aren't necessarily feasible in living organisms... I'm still reading the (OP) article.

    I don't understand this argument.

    Fermentation of pyruvate into lactic acid (which itself is a buffer that can be turned back into glucose) simply regenerates the NAD+ that was consumed during formation of pyruvate in the first place. This process cannot generate excess NAD+ to feed other oxidation reactions. Meaning what they are suggesting is simply a transient/temporary process, rather than an equilibrium process.

    Secondly, oxidation reactions such as during fatty acid metabolism don't preclude regeneration of NAD+ given the shuttles mentioned above.

    On further reading, they experimentally induced a condition where the mitochondrial membrane potential built up to high levels, leading to increased function of Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP). This is basically acting as a relief valve that reduces the membrane potential, but bypasses the electron transport chain, thus limiting ATP production. This also uncouples NAD+ regeneration from the electron transport chain (bypassing the aforementioned shuttles).

    A big weakness in their study is they don't actually show how this hypothesised NAD+ deficiency occurs naturally. In this study, they haven't demonstrated increased fatty acid metabolism or other oxidative pathways.
    Experimentally they inhibited Pyruvate dehydrogenase kinases (PDK) using pharmacological agents and CRISPR. These kinases inhibit pyruvate dehydrogenase (PDH) through phosphorylation. Normally PDKs play a key role in PDH regulation, since NADH & Acetyl CoA in turn positively regulates PDK activity. This coupling is already known and is key to the whole process.


    As such, little in this paper should be considered particularly surprising.

    The abstract could read very differently if written by another author - PDK inhibition removes the necessary feedback loop regulating PDH activity, leading to a high membrane potential, leading to activation of FCCP and a loss of ATP and NAD+ generation in the mitochondria. Or more simply put, the disruption of the regulation of mitochondrial respiration leads to increased lactate production. It doesn't sound so surprising when stated like that.
     
    Last edited: Dec 31, 2020
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