Raphi tweeted this paper recently
Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS
which is nice provided, as he comments, it can be replicated. There is absolutely no possible conflict of interest anywhere so long as you accept it looks like an in-house Nestlé study. I haven't knowingly bought a Nestlé product in over 30 years.
Anyway. The study looks at healthy brain biochemistry under MCT induced ketosis. The ketone oxidation (or possibly the CNS oxidation of MCTs) increases the NAD+:NADH ratio, ie moves it in the Good direction.
There is a lot of talk about the NADH generation and NAD+ depletion during glycolysis to pyruvate, shifting the ratio in the Bad direction. The assumption (with which I disagree) is that the glycerophosphate shuttle is a rescue mechanism to regenerate essential NAD+ to allow glycolysis to continue, to which I will return in a moment.
The beauty of ketones is that they do not deplete cytoplasmic NAD+ at all and only consume one mitochondrial NAD+ during the conversion of BHB to AcAc. Because this happens within the mitochondria this, plus any NADH generated at the pyruvate dehydrogenase complex, is sitting next to complex I, the most prolific re-generator of NAD+ in the cell...
All well and good and bully for ketones and the manufacturers of Peptamen®1.5 Vanilla (Nestlé Health Science SA).
This got me thinking.
Of course no one in their right mind would expect glycolysis to be arranged in such a manner as to require the glycerophosphate shuttle for simple NAD+ regeneration. This is a wasteful loss of four pumped protons and this energy will appear as heat. Think of brown adipose tissue, full of mtG3Pdh, assuming insulin is plentiful. The correct pathway for the metabolism of glucose without insulin is to lactate without any overall depletion of cytoplasmic NAD+. Lactate can then be taken up by mitochondria exactly as ketones are. Lactate will, in the mitochondria, be reconverted to pyruvate, depleting mitochondrial NAD+ in exactly the same way as the conversion of BHB to AcAc does. Equally this happen right next door to complex I, just waiting to regenerate NAD+ and keep that NAD+:NADH ratio nice and high.
The whole point of the glycerophosphate shuttle (in Protons terms) is to facilitate insulin signalling. Insulin is the hormone of plenty, used to encourage caloric ingress in to cells. Loss of the four pumped protons due to bypassing complex I and using mtG3Pdh instead as part of insulin signalling appears perfectly reasonable under conditions of active caloric ingress. Sustained insulin signalling causes sustained loss of cytoplasmic NADH, which generates NAD+. Once this has happened there is no longer the surfeit of cytoplasmic NADH over NAD+ from glycolysis, which is essential to drive lactate formation. Glycolysis must therefor stop at pyruvate under insulin.
Summary: For insulin signalling the glycerophosphate shuttle is active and loss of NADH requires glycolysis to abort at pyruvate.
Without insulin signalling glycolysis runs to lactate which enters mitochondria without any depletion of cytoplasmic NAD+. The lactate should enter the mitochondria, under normal physiology.
Sooooooo. This had me thinking about what would happen if, in the presence of copious glucose and copious oxygen, there was to be a sudden profound fall in absolute insulin levels. I was particularly interested in systemic lactate levels.
A sudden, profound fall in insulin levels in the presence of glucose is pathology. It generates ketoacidosis, classically from acute beta cell destruction during the onset of DMT1. There is always a profound metabolic acidosis from the failure to suppress glucagon-induced lipolysis and subsequent massive acidic ketone generation. Under the canonical view the absence of insulin should not stop NAD+ regeneration by the glycerophosphate shuttle.
What I wanted to know was whether the Protons predicted shutting down of the glycerophosphate shuttle due to hypoinsulinaemia would result in diversion past pyruvate to lactate as the end result of glycolysis. In the presence of massive levels of ketones I would also expect this lactate to appear in the systemic situation.
Does it?
Yep. Ten seconds on Google says so.
Lactic acidosis in diabetic ketoacidosis
Very nice. I had no idea this was the case because it has no direct influence on treating DKA clinically...
Peter
Of course you have to think about the chicken and egg situation with insulin and mtG3Pdh activation (I have been for years!). Which comes first? I think insulin appears to be essential, as above. I do wonder if the insulin receptor will turn out to dock with the glycerophosphate shuttle in some way...
This is fascinating, although I struggle to keep my head above water in terms of understanding the finer points. Also the medium points. As well as some of the larger points.
ReplyDeleteSo it may help if you could give an example of what might cause such a sudden profound fall: "This had me thinking about what would happen if, in the presence of copious glucose and copious oxygen, there was to be a sudden profound fall in absolute insulin levels."
Thanks!
cavenewt,
ReplyDeleteI'm with you on the physiology. I have to read very carefully just to keep up, and even then it's quite a brain-teaser. My excuse of course is that I'm a lay reader of Peter's thinking. And he will always know more than I can ever learn from him.
I think the example was the 22-year-old T1 diabetic in the second paper. He either missed his insulin shot or gave himself too little and went into DKA. They found lactic acidosis and speculated as to why.
The post demonstrates the predictive power of the Protons thread concepts, at least concerning the glycerophosphate shuttle, which indicates Peter's been on the right track.
Schurr proposes that the end-product of glycolysis is always lactate and that pyruvate is obtained outside of the glycolytic pathway with LDH (or mLDH) doing the conversion. I find his model of glycolysis more convincing than the textbook 'branching' model giving either lactate or pyruvate. see here for his paper "Cerebral glycolysis: a century of persistent misunderstanding and misconception" http://www.ncbi.nlm.nih.gov/pubmed/25477776
ReplyDeleteI bring this up because, I wonder, does it change anything to what you say here?
"Once this has happened there is no longer the surfeit of cytoplasmic NADH over NAD+ from glycolysis, which is essential to drive lactate formation. Glycolysis must therefore stop at pyruvate under insulin"
I think not, but im not sure...
I also think Schurr's model of glycolysis might be more congruent with the Proton's line of thinking to explain the situation where there's high glucose + high oxygen + super low insulin = lactic acidosis + ketoacidosis
if lactate is always the end-product of glycolysis then this circumstance is arrived at more directly than with a branching model of glycolysis (i think...)
Ah raphi,
ReplyDeleteWhat an enjoyable read! Your comment neatly ties together the primacy of lactate and the evolutionary context of insulin.
So. Glycolysis should run through from glucose to lactate without any branch to mtG3Pdh and so never give a requirement to accept pyruvate as the core mitochondrial fuel. Mostly.
Insulin. Insulin should be used primarily as cross talk between the pancreas and the liver. I’d have to go to Kraft’s work on what level of systemic insulin he considers pathology and I’ve loaned his book out to somebody. Insulin has no right entering the systemic circulation at 10,000picomoles. Probably not even 1000picomoles. If we accept that carbs were commonly consumed during evolution we would expect those carbs to be fibrous and never to deliver bulk glucose/fructose to the liver in quantities or speeds which allow penetration past the liver and in to the systemic circulation, requiring an emergency insulin dump from the pancreas to re-establish normoglycemia. This is pathology. Maybe honey is the exception for which a pathological level of insulin might be needed to deal with a human gather-able foodstuff…
So insulin, above basal levels, has limited role in the systemic circulation on an ancestral diet. Insulin signalling should be a minor player in a diet based around large herbivore fat. The glycerophosphate shuttle should only be as active as the low levels of insulin require, ie not very active. Pyruvate supply to the mitochondria should be low and Schurr’s beloved lactate should be the core mitochondrial fuel. Mostly.
No one should ever secrete so much insulin to induce insulin-induced-insulin resistance. I would think of the glycerophosphate shuttle as a sensor or emergency pressure valve. Not a bulk throughput but important for regulation of calorie ingress never the less. Nowadays it is so active that it has, to Schurr’s dismay, taken pride of place as “normal” glycolysis. Today it is normal. Today we have pathology.
Wadyathink?
Peter
Bob and cave, be back soon
ReplyDeletePeter
Deeply interesting although I am struggling to understand. Peter and/or Raphi, any thoughts about how how Schurr's model might relate to the Warburg hypothesis eg the nice diagrams to base pondering on at Richard F.'s blog
ReplyDeletehttps://feinmantheother.com/2016/12/04/ketogenic-diets-for-cancer-iii-more-background-and-the-warburg-effect/
@passthecream
ReplyDeletei don't know if it really makes a difference to the metabolic theory of cancer - i don't think it does but i can't say i've spent a lot of time thinking about the implications of Schurr's model on this point. Schurr's model of glycolysis is more elegant though :) ... if you want to understand more about cancer and the metabolic theory i recommend Peter Attia's recent podcast with Thomas Seyfried https://peterattiamd.com/tomseyfried/
Seyfried is decades ahead of 99% of cancer researchers out there. even if his particular view of the metabolic theory turns out to be wrong he will still have been invaluable in mounting an air-tight case against the somatic mutations theory (SMT) of cancer simply belongs to the scientific graveyard.
At the risk of exposing my ignorance: if glycolysis always proceeds to lactate with Ox or without it (Schurr), and lactate is the tca input rather than pyruvate, it seems that the picture shifts to the underutilisation of oxygen and lactate by mitochondria rather than the overproduction of lactate by glycolysis. Faulty respiration, which is Warburg's main idea anyway.
ReplyDelete"If you are post-obese, via low carb eating, there is every likelihood that repeatedly consuming the chips (to avoid the pancreatitis, don’tchano) will cure you of the post-ness of your obesity. Enjoy the chips by all means." -- Peter, on Ketogenic diet: Eat food
ReplyDeletePeter, you are getting increasingly acerbic, and thus ever-more-devastatingly funny. I guess we need a bit of bile to digest all the fat. At any rate, better to fulminate against carbs than to have fulminating pancreatitis.
Just wanted to say thank you for your continuing higher-level cranky-man analysis, it is a real treat, even if most of it goes over my head and I have nothing of biochemical import to impart. Either way, your blood's worth bottling. Have a great Christmas break, and a wonderful 2019.
@Peter
ReplyDeleteGlad you enjoyed. You can tell Schurr has a chip on his shoulder - I love it!
It's a really interesting point about mtG3PDH being an energy sensor/pressure valve rather than a bulk substrate delivery machine. I need to think through some of the implications...
@passthecream
ReplyDeletelactate doesn't get into the TCA cycle but it does get into the mitochondria where it can then be turned into pyruvate. that lactate to pyruvate conversion can also happen in the cytosol (outside the mitochondria). there's a few nice diagrams in the Schurr paper I linked to if you want to have a graphical explanation of this
indeed, this fits nicely with the Warburg Effect. think of it this way: if you have faulty mitochondria and can't couple the electron transport chain to ATP production, but you still have 'activity' in the mitochondria, you're going to get
(a) a ton of lactate build up (since glycolysis proceeds to lactate)
(b) the ETC is still 'moving along' and oxygen is still flowing through the mitochondria, giving a false impression of normal ox phos
(c) lots of ATP is still available, and coming from mitochondria, but actually through ox phos but through substrate-level phosphorylation (SLP) instead
=== SLP depends on glutamine being sucked up through the alpha-ketoglutarate port of entry into the TCA cycle
this is what cancer researchers are missing. they don't understand SLP and don't design experiments that adequately control for it. they just say "oh hey lots of oxygen in the mitochondria, lots of ATP, oxphos is fine, nothing to see here move along. no faulty mitochondria"
and more expensive and useless "genotyping" and chemo and radiation is done without any real progress
a tragedy if there ever was one
Raphi I am slowly working my way through Seyfreid's book atm. Very slowly. He has a bigger chip on his shoulder than Schurr for good reasons I think. It's all way above my pay grade anyway. :/
ReplyDeleteYou might find this older work interesting, nice differential equations and loads of lovely reaction constants in a very dense paper which combines spahetti with alphabet noodles. (You could install Modellica and just plug them all in.)
The effect of 5mM salicylate on liver mito. TCA is quite dramatic in their model, turns it into a short loop powered by transamination via glutamate, looping back from a-ketoglutarate, disables succinate dehydrogenase also.
Trying to digest that idea together with Seyfreid's ideas is interesting. In some ways it resembles his idea of faulty ox-phos but it seems to sidestep the extra atp from fermentation. Is that good or is it bad?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651525/
Curious what's your take on the Seyfried podcast Raphi linked above. He seems hellbent on respiratory damage, but doesn't explain why that would lead the cells to start proliferating.
ReplyDeleteI just saw an explanation in Peter's notes (Attia) towards the bottom of podcast's page but still can't make sense of it.
ReplyDelete@altavista
ReplyDeleterespiratory damage leads cells to protect itself according to what evolution taught it. it does so via a mechanism called the retrograde response. there's much to say about it, but essentially it's the cell's 'safety protocol' where it reverts to a primitive metabolism, a metabolism of fermentation. Physicist Paul Davies & colleagues term this the 'atavistic model' http://www.ncbi.nlm.nih.gov/pubmed/28750585
Raphi, I get the reason for the metabolic shift to fermentation, but why do they start proliferating? Seyfried only mentions in passing they lose their killswitch, duh. Those diagrams in the notes are above my level.
ReplyDeleteThe other podcast with Navdeep Chandel, who actually did the experiments, unlike Seyfried, is better. Knocking out complex 1 in cancer cells, proves mitochondrial function (respiration) is necessary for tumorigenesis so they kinda respire unfortunately.
@altavista
ReplyDeleteProliferation isn't actually understood all that well. But apparently there's something about gung-ho primitive fermentative metabolism breaking cells in a way that causes a shit ton of widespread damage to the cell's nuclear DNA that otherwise gives the cell's default as 'stasis' rather than 'proliferation'. A for metastasis, the spreading of the cancer, Seyfried & co propose immune cells are involved. immune cells are spread throughout the body, that's sort of what cancer cells do, and they sometimes follow patterns of travel that are identical to immune cells. so Occam's razor is that cancer cells spreads when immune cells finally suffer the metabolic insult threshold turning them cancerous.
raphi and alt,
ReplyDeleteI'm only part way through the webcast but I would just point out that I have a huge problem with glycolysis being describes as "primitive". Ox phos is one of the core process of emergent life. That's primitive. CODH/Acetyl-CoA synthase is equally primordial, making acetyl-CoA or more likely acetyl phosphate as core to the supply of acetate to the TCA and subsequent ox-phos. Glycolysis looks like a big, clunky, multi enzyme mess designed to deal with glucose sourced from photosynthesis. As such a non photosynthetic cell views this as it got lucky and takes it as a signal to grow and divide... I don't have the ref but I am aware that normal rapidly dividing cells utilise aerobic glycolysis as part of the division process. I'll pull up the refs and write a post one day
Peter
I would just add that in the case of Pablo Kelly, the n=1 case Seyfried mentions in the podcast, unfortunately the tumour has apparently re-formed as of Dec 2018 according to the scan he posted. This despite the 2017 surgery and his valiant efforts to increase his keto state.
ReplyDeleteIt's beyond belief this matter (Warburg) is not settled in 2019.
@Peter
ReplyDeleteAs I understand it, here 'primitive' refers to phylogenetic order: fermenters when the atmosphere was poorly oxygenated, then photosynthesizers started spitting out oxygen into the atmosphere, thus allowing the rise of respiring organisms. Of course, the intermediate steps muddy this whole picture, but that's the gist of it. Maybe I'm missing your point though, because I don't see how ox phos can be more primitive than fermentation (not glycolysis per se) - except if we take substrate-level phosphorylation as fermentation in mitochondria. Still, mitochondria in their present state are only useful in an oxygenated atmosphere...right?
You say "normal rapidly dividing cells utilise aerobic glycolysis as part of the division process" and that's spot on. There are many of those instances where fermentation appears to be a 'grow and divide' signal.
@altavista
Oh shit! Can you link to where you find this out? Thanks
raphi,
ReplyDeletehttps://www.sciencedirect.com/science/article/pii/S0005272809000048
if we go back to the earliest ox phos, best preserved in highly evolved form by A woodii today, we have hydrogen providing electrons via electron bifurcation to give reduced ferredoxin. The red-ferredoxin can be re-oxidised to ox-ferredoxin by the Rnf complex (which includes the subunit ferredoxin:NAD+-oxidoreductase) reducing NAD+ to NADH in the process. This is speculated (not proven, but it will be) to involve the pumping of a single Na+ ion in the process. The Na+ gradient is then available to turn a Na+ATPase and generate ATP via chemiosmosis.
This oxi-reduction reaction is clearly a very early ox phos using a Na+ gradient. The fact that, should you so wish, you can bolt on a string of cytochromes to continue the tracking of electrons down the massive chemical gradient from NADH to the terminal acceptor O2 (once it becomes available from oxygenic photosynthesis) is simply an add-on which never appealed to A woodii. Of course using cytochromes favours a proton gradient but in no way precedes the oxi-reductive pumping of Na+.
I can see that the ancestor of A woodii may well have generated glucose and used glycolysis as the reverse of the synthetic pathway but, without photosynthesis, it would have needed to supply all of its ATP needs from ox phos using the ferredoxin:NAD+ oxidation-reduction reaction (plus see below). This ATP would be used to generate the glucose in the first place. Clearly ox phos precedes both glucose metabolism by a sort time and photosynthesis by a very long time.
The modern ox-phos of mitochondria based around acetyl-CoA and the TCA in addition to beta oxidation is also preceded by the generation of acetyl-phosphate or acetyl-CoA supplying the TCA (which may well have been more anaplerotic and not necessarily cyclical) from the Wood–Ljungdahl pathway, again using red-ferredoxin from electron bifurcation to generate the acetyl moiety, core to emergent life… A woodii simply converts the acetyl-CoA to ATP and acetate and dumps the acetate as waste.
The role of fatty acids for beta oxidation is also interesting and may well have been one of the core challenges at the formation of eukaryotes. Dr Speijer has looked at this in the development of the peroxisome by LECA. Of course beta oxidation could be as primitive as glycolysis, simply being the reverse process of their synthesis for structural purposes (using ox phos to generate the necessary ATP).
Sorry to rabbit on but that’s how I see evolution. You did ask! I guess it depends on what you mean by primitive.
Peter
@Peter
ReplyDeleteWow thanks for the detailed answer, that helps a lot. I feel it deserves its own blog post though...
So the Rnf complex-ferredoxin interaction is the version 1 of ox phos, the primitive one. With that as the new standard it's certainly older than multi-step glycolysis. I'm thinking out loud, will it affect my view of fermentation and cancer? Maybe it reframes the question as, what is it about ox phos that allows the default to be stasis?
Well, there is also Ech, energy conserving hydrogenase, the great-great etc-great-grandpappy of complex I. This is a hydrogenase which used to use the geothermal gradient to generate rd-ferredoxin before electron bifurcation was evolved. The membrane portion of this duplicated and probably gave rise to the Na+/H+ antiporter which was transfered to Rnf to pump Na+ (my speculation here). Nick Lane considers that Ech gave complex I pump of bacteria and Rnf was evolved by the archaea, with lateral gene transfer to the A woodii family. I think. I can't quite recall what he considered and what I derived from my own considerations. But essentially ox phos ran on rd-ferredoxin and one of two Na+ pumps.
ReplyDeleteI have a pointer to the basic consideration that glycolysis drives proliferation and ox-phos is for maintenance but I've not followed this concept very far. A major activated-without-mutation driver of cancer growth is Myc as in https://www.ncbi.nlm.nih.gov/pubmed/29706933 Obviously Myc is activated by, err, insulin signalling amongst several other factors https://www.ncbi.nlm.nih.gov/pubmed/18463697…
You have to wonder if the benefits of ketogenic eating, such as they might be, derive from glycolysis suppression/growth factor suppression rather than a direct mitochondrial effect. I’m wondering along these lines but I really don’t know. It’s early days…
That will be geochemical rather than geothermal!
ReplyDeletePeter
Hi alta, I pubmeded Chandel, complex I and cancer and got these three hits:
ReplyDeleteMitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells
https://www.ncbi.nlm.nih.gov/pubmed/29617673
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
https://www.ncbi.nlm.nih.gov/pubmed/24843020
Reductive carboxylation supports growth in tumour cells with defective mitochondria
https://www.ncbi.nlm.nih.gov/pubmed/22101431
The Pten-null cells are using ATP synthase in reverse to utilise ATP from glycolysis to generate anabolic substrates and I would guess need NAD+ to continue the process, complex I being needed even if it doesn’t send electrons down the ETC.
The metformin doses are astronomical in paper 2 and will at least be blocking insulin signalling in addition to stopping NAD+ regeneration in the cytoplasm (via the glycerophosphate shuttle).
The third paper describes the classical glutamine fermentation to generate anabolic precursors.
Am I missing anything more specific?
All the best
Peter
Peter, to me #2 shows seyfried is wrong, but they wrote a 2016 paper that has all the refs (bioenergetics section) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928883/#!po=13.2813 and there is a summary at the bottom of https://peterattiamd.com/navchandel/
ReplyDeleteRaphi, he's on facebook at https://bit.ly/2SFcWeO
Hmm, I thought paper 2 looked familiar!
ReplyDeletehttps://high-fat-nutrition.blogspot.com/2017/11/metformin-03-in-vivo-experiments.html
Peter
atl, I think the core question we have to answer is why, if metformin works as an anticancer drug by blocking complex I (which I absolutely do not believe), was it necessary to engineer in NDI1 to the cancer cells? Chandel clearly, absolutely, understands the importance of the NAD+:NADH ratio. But he thinks metformin works by blocking complex I in-vivo, a manoeuvre which will sky-rocket the level of NADH in the mitochondria? So he also knows enough to reduce the NADH levels by engineering in NDI1... Simply knocking down complex I should absolutely mimic metformin's action if he is correct. Don't you feel uncomfortable with the random choice of engineering in NDI1? Smells like there is an old dead fish somewhere in the fridge to me.
ReplyDeletePeter
Peter, I'm not saying Chandel is right (about metformin), I'm saying Seyfried is wrong (about glycolysis/slp).
ReplyDeleteIf Seyfried is correct, whatever Chandel is doing at complex I (metformin, aspirin or whatevs) shouldnt have an effect on tumours, because they have reverted to glycolysis/slp, no? But it does.
So saying he can stress the poor cancer cells with keto (then kill them with glutamine inhibitors pulse) doesnt work because the cancer has other sources of energy, which jives with the 2016 paper above.
Now he also has to explain Pablo Kelly who was in keto the whole time, 3 years before and 1 year after surgery. I bet nobody in the world is in deeper keto than him, yet the tumour has apparently grown back, which again jives with the 2016 paper.
Anyway they address your question in the podcast around the 1:10:00 mark i think, where he says they did that exact experiment.
@Peter
ReplyDeleteI'm interviewing Dominic D'Agostino on my podcast today, so I'll read Navdeep Chandel's paper NDI1/metformin paper and ask your question :)
@altavista
ReplyDeletethanks. hope Pabo beats it a 2nd time. he said he's getting help to optimize his own protocol, good for him
in Chandel's bioenergetic on cancer, he says "many studies have demonstrated that the great majority of tumor
cells have the capacity to produce energy through glucose oxidation (that is, the process by which glucose-derived carbons enter the TCA cycle and are oxidized to CO2, producing ATP through oxidative phosphorylation)" ==> currently, that's factually incorrect.
This whole premise motivated my MSc thesis and experiments; i purposely chose cells that appear to falsify the Warburg Effect best, like MCF-7 breast cancer cells that have intact OxPhos according to Guppy et al.
1) all experiments i've seen so far supporting Chandel's claim, without exception, fail to control for substrate-level phosphorylation (SLP). Basically, mitochondria appear to be working because oxygen is fluxing through them when in reality ATP isn't produce due to OxPhos but through glutamine fermentation entering the TCA through alpha-ketoglutarate
2) the MCF-7 cells i prodded in vitro with a variety of metabolic inhibitors all showed extremely high lactate-to-pyruvate ratios, the unmistakable signature of aerobic glycolysis (Warburg Effect) which, so far, has never been shown to happen with mitochondria retaining their ultrastructural integrity
A) if Chandel or otherwise control for SLP and get the same results, i'll be wrong.
B) if we identify transformed with intact mitochondria, i'll be wrong.
C) if it can be shown that the nuclear-cytoplasm transfer experimental results can be, somehow, reconciled with the somatic mutations theory of cancer, i'll be wrong.
Until then....
raphi, would you be so kind as to provide a link? I don't know what your podcast is. Thanks.
ReplyDelete"I'm interviewing Dominic D'Agostino on my podcast today..."
Raphi, here is what happens when you knockdown a gene essential for assembly of complex I without engineering in NDI1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671602/ Clearly, if metformin in-vivo ever managed to block complex I significantly I would expect the resulting cells to act like an NDUFB9 knockdown population. Not so good.
ReplyDeletealt, I'm ambivalent about Seyfried and clearly some of the data in the paper do suggest that oxygen consumption is reduced by metformin, so I can see where you are coming from. I'm still uncomfortable about certain aspects even of the oxygen consumption data and I would also say that I would not be surprised to find that life is a spectrum with the aggressiveness of a cancer increasing as its ox-phos deteriorates. Must try and listen to the rest of the discussion you linked to.
Peter
@cavenewt
ReplyDeletehere are my podcast episodes from last year https://www.breaknutrition.com/podcast/. I recorded one with D'Agostino today but it isn't out yet. i can let you know when it's out on Twitter (@raphaels7)
@peter
ah, nice abstract. It seems we can replace Complex 1 with NDI1 and thus decrease ROS (longevity), or add accessory subunit NDUF89 to Complex 1 and thus increase ROS (tumorigenesis). interesting
@altavista ["Now he also has to explain Pablo Kelly who was in keto the whole time"]
ReplyDeleteSeyfried says that mitochondrial substrate level phosphorylation (mSLP) drives a lot of GBM growth. He may have said something to the effect that, 'GBM are glutamine hogs,' and says that you probably need a drug (like DON) to lower glutamine to therapeutic levels.
Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis
Press-pulse: a novel therapeutic strategy for the metabolic management of cancer
Would LOVE for @peter to read the 1st paper above and get thoughts on mSLP.
Bob, he got the treatment from Seyfried (at around 2:25:00 podcast) so I presume he used the glutamine stuff to. I just said keto to simplify.
ReplyDeleteThen the puzzling question for me is why keto worked the first time (2014-17) making the tumour operable, but after the surgery the fcking thing relapsed, on even deeper keto? And press-pulse presumably. It has to be energy adaptable.
Hopefully that scan was wrong and they redo it.