Saturday, January 25, 2014

An aside on psychiatric links from Sid Dishes

Sid has recently put these two excellent links up on her Facebook timeline. The Protons thread is slowly working its way towards probable causes of complex I failure and an awful lot of the basic mitochondrial information comes from papers on Parkinsons disease or Alzheimers disease.

It has been clear for some time that many, many mitochondrial problems, when localised in specific sets of neurons, are categorised as psychiatric illnesses without needing to have a full blown genetic mitochondrial disease at their core. Acquired mitochondrial dysfunction, most likely at complex I, might well be all you need. Have the right SNPs in genes for proteins of the ETC or assorted ion channels might allow you to be allocated schizophrenia, bipolar disorder or major depression as your pigeonhole.

Trying to treating mitochondrial psychosis by tinkering with the superficial knock on effects at the neurotransmitter level will be of limited effectiveness. Altering bioenergetics using an NAD+ precursor or by inducing ketosis might be far more logical approaches.


The psychiatric presentation of mitochondrial disorders in adults

Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra.

The second paper is a rather broad brushed picture of evolution, society and NADH. Gross NAD deficiency with adequate calories (pellagra) will mean that there is almost no time for NAD+ to exist before being reconverted to NADH. The high NADH/NAD+ ratio will particularly favour excess superoxide generation at complex I if there is any reverse electron flow from the CoQ couple. It's a pity this paper does't have mtG3Pdh in its diagram of the ETC. An interesting read even if it's full of concepts which the Hyperlipid perspective might question or might invert the causality there-of.

EDIT: I found this one myself and nearly lost it. The perils of PubMed-ing in your lunch break at work and not emailing the link to yourself!

Neuroanatomical Pattern of Mitochondrial Complex I Pathology Varies between Schizophrenia, Bipolar Disorder and Major Depression




James said...


Sorry for changing the subject. Could anyone could refer me to some resources on ketosis as a therapeutic against brain cancer? I have a friend who has this type of cancer and doesn't even really know what ketosis is so I'm trying to give him some stuff with which he can inform himself. I know this has been asked before on this blog but I'm wondering if there is any stuff specifically for brain cancers. Thanks.

Sabine said...

Hi James,

I am sad to hear this of your friend.
You may want to start with this:

This webpage is by a Dr. Seyfried, who is doing research in this area.
The diet is a calorie-restricted ketogenic diet.
And Simply searching the internet will lead to many results.
There are also lectures on YouTube.
Hope this helps.

Puddleg said...

New human study on PQQ:
"Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects"
Note that TMAO is one the markers improved. That had zero to do with red meat consumption BTW.

@ James, also have a look at this possibility (if it's a glioblastoma)
from the latest Life Extension e-mag. I'm sure there are cheaper drugs effective against cytomegalovirus.

Neil F said...

James. Just to add more info about Dr. Seyfried. His textbook, "Cancer As A Metabolic Disease" goes into great detail about the treatment of brain cancer in the final chapters of the book. It is essential reading.

raphi said...
This comment has been removed by the author.
raphi said...

Speaking about psychiatric stuff ---> But I thought pot killed brain cells and made people crazy?! Oh, wait..."The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme"

[Homer-druling-over-a-donut-voice] Hhhhmmm cannabis induced ketosis...

Not sure how this links into mitochondrial complex selection, exactly, though...

Unknown said...

Peter have a look see to where our collision course is: Where electrons and protons in mitochondria meet:

Unknown said...

Peter said, "Altering bioenergetics using an NAD+ precursor or by inducing ketosis might be far more logical approaches." Now to this: when nuclear levels of NAD+ are low, a sequence of events occurs in the cell nucleus that ultimately results in a lack of adequate expression of mitochondrial DNA genes that are required for Complex I, III, and IV in mitochondrial electron transport. In this scenario, the nuclear-encoded proteins required for mitochondrial electron transport chain are still expressed, but the proteins whose genes are encoded only by mitochondrial DNA are not expressed. Thus, mitochondrial electron transport cannot occur and cells develop a metabolic picture which is "typical" in cancer, which is called the Warburg effect. With Warburg-type metabolism, cells do not generate ATP from the mitochondria and instead, become dependent on cytoplasmic generation of ATP via aerobic glycolysis. The primary driver of this “metabolic reprogramming” is the transcription factor, Hypoxia Inducing Factor 1 alpha (HIF-1α), which normally only activates Warburg-type metabolism when oxygen levels are low. Hypoxia has major effects on mitochondrial efficiency and biogenesis. Signaling is a big deal in this case because superoxide generation is altered. When nuclear NAD+ levels are low, HIF-1α is stabilized and is not degraded by VHL as would normally be the case. Here is the link to VHL and the ubiquination pathways.

Unknown said...

When all these things happen Peter in simultanity, as occurs in our modern world, cells are “metabolically shifted and reprogrammed” to use aerobic glycolysis in the presence of normal oxygen. HIF-1α inhibits a chain of events that ultimately results in a reduced expression of the mitochondrial transcription factor, TFAM, which normally migrates from the cell nucleus to the mitochondria to stimulate mitochondrial DNA replication. As a result, mitochondrial encoded genes are expressed. When HIF-1α inhibits TFAM, this does not occur. This is a big assed deal. These circumstances allow nuclear encoded mitochondrial proteins still to be created via the transcription factor Nrf1. But where the rubber meets the road is with TFAM. When TFAM is suppressed by HIF-1α NO mitochondrial-encoded protein components of the electron transport chain are expressed at PERIOD. This results in mitochondria that cannot make ATP at all, but they still have defective ECT that “run in reverse”. You and I have mentioned this quite a bit on both our blogs. The significance is, as you know of unfettered “reverse electron transport” results in the production of uncontrolled amounts of negatively charged free radicals from the mitochondria. This enhanced charge destroys the pH gradient of the proton motive force in mitochondria to destroy proper redox signaling. The charge on the inner mitochondrial membrane drops quickly. This then creates the “Primordial molecular signal of aging and disease” we see in experiments. The signal is mitochondrial dysfunction with a higher free radical production. All of these events can be traced back to inadequate NAD+ in the nucleus. You and I been saying it but using different science to get the word out. Without adequate NAD+ in the nucleus, SIRT1 cannot function. why is this a big deal? It turns out NAD+ is a mandatory co-factor for all of the proper functioning of sirtuin signaling. This is why the sirtuins have there own "levee" in my Quilt document. The article in Cell by Sinclair is a master piece.

Unknown said...

Sinclair et al are now using Niagen to replace NAD+ because it is cheaper than NMN which is biochemically one step closer to NAD+ synthesis. NMN is very expensive to make so it has no long term business viability. Sinclair can not afford a misstep because he swindled Glaxo out of 700 million dollars for his resveratrol researcher. The next bog pharma company wont pony up because of it. I personally think Sinclair is going to make his own biotech company and mass produce the Niagen for his own pockets. It may be the best weapon humans have to battle high carb diets mixed with the effects of non native EMF's on the ETC. The work is stellar but I remain a skeptic on Sinclair because of his history with Galaxo.......but his science matches up with my findings and what Peter is saying here on his blog.

Unknown said...

People across the world are waking up that quantum tunneling of electrons is directly linked deficiency of NAD+ in the nucleus of cells. This produces a state of “pseudohypoxia”, where there is adequate oxygen but high levels of HIF-1α. When quantum tunneling is affected so are the ways protons are handled in mitochondria. This ultimately results in the inhibition of the mitochondrial transcription factor (TFAM) which inhibits the expression of mitochondrial DNA which is located right next to cytochrome one. As a result of this "shift", mitochondria can not and do not produce the proteins encoded in mitochondrial DNA that are required for “forward electron transport” and normal ATP production. When this happens proteins can not be unfolded maximally to allow water to behind these proteins for proper energy transfers. Gilbert Ling's work here. All proteins must have proper hydration cells to work well. The same thing is true of mitochondria. They must have water surrounding them to transfer energy from protons and electrons to fuel biochemical reactions. When they do not reverse electron transport occurs and high levels of free radicals are produced, giving the exact picture of aging and neolithic disease generation. In this metabolic scenario cells are dependent on aerobic glycolysis in the cytoplasm and cannot burn fat well. Cytochrome 2 is their bail out. Here is where fats can still be handled. This is why ketosis is protective when this "shift" occurs. These cells develop the exact metabolic picture of cancer, well known as the "Warburg effect." The Sinclair paper shows that mitochondrial dysfunction and this Warburg-type metabolism are fully reversible with the supplementation of NAD+ precursors. Ketosis is protective because it allows passage of electrons and protons from fats to make some ATP and salvage the bad mitochondria.

Peter said...

Hi Jack, just downloaded Sinclair's paper. Ta. Many of the concepts you mention (pseudo hypoxia for one) are on the To Do list of long, long standing.

Ultimately there are a set of concepts about how things work. Ideas should converge...


Puddleg said...

@ raphi,

carnitine palmitoyltransferase I is upregulated in the brains of schizophrenics.
- see fig 2
They already have keto-brain for some reason.
(Maybe better to go with this flow).
Odd because DHA is protective against psychosis and is precursor for anandamide antagonist.

But cannabis for pertussis... might just work. imagine the implications if babies' lives were being saved in this way.

Puddleg said...


deficiency of NAD+ is easily corrected by degradation of tryptophan by IDO and TDO; ergo, reductive stress can drive low-serotonin depression.
But cytokine messengers mediate this, so process is also inflammatory.
So instead of inflammation driving depression, reductive stress - basic metabolism - may drive both.

callingnew said...

Mind altering microorganisms: the impact of gut microbiota on brain and behavior Includes info on tryptophan disruption (implicated in pellagra)

raphi said...

@George Henderson,

I went through that paper, reallllyy interesting!
It’s a great (albeit frustrating) example of how difficult it is to establish cause & effect - did the up regulation of enzymes/proteins/pathways specialised in mopping up ROS’ appear as a damage control mechanism or is it a natural change accompanying a alternate mitochondrial fuelling?
It makes a lot of sense to me that our brains would be able to adapt our mitochondria to utilising a predominantly non-glucose substrate following problems in glucose/oxygen utilisation. If we didn’t - we wouldn’t look like the resilient species that we are!.

The excellent track-record of pot in treating symptoms of demyelinating disorders + its in vitro ability to induce ketosis (or at least keto-adjacent mechanisms) starts to weave an intriguing web…

Well babies/children with epilepsy (& other disorders) are already seeing incredible symptom management with CB2 oils (devoid of THC) with nearly 0 side effects. Food for thought

Peter said...

Blogger ate my comment. @£$%^!!!!


raphi said...


I read the paper you linked to - marvelous! So many ideas, so little time & data, moooorreee, give me mooorreee!

Hypoxia is obviously an event our body has planned for with multiple back-up pathways...we seem to have issues resolving it when it occurs in chronic low-grade forms. I think Dr.Dominic D'Agostino might be of interest with this specifically as he studies ketogenic diets in relation to their potential in aiding deep sea divers and soldiers when they're face with the potential for hypoxia [he was recently on Dave Asprey's BulletProofRadio podcast thingy majig...]

James said...

Thanks Sabine, Neil, and George. The links have all been helpful.

Unknown said...

Hi Peter,
I'm kind of confused on the role of superoxide in mitochondrial function. I know that, in excess, it is damaging but it is also important for physiological insulin resistance and mitochondrial bio-genesis. I've seen you state that an overly reduced CoQ pool causes excess superoxide production through reverse electron flow through complex 1, which can be harmful. I've seen you suggest that this is why we should avoid glucose metabolism, which drives complex 1, which you've stated is quite leaky, and thus produces superoxide. However, studies you've provided suggest it is only reverse electron flow through complex 1 which causes this excessive superoxide production, resulting in insulin resistance and fat metabolism produces far more superoxide than glucose metabolism, even through the leaky complex 1. So if we want to avoid "leaky" mitochondria, which you've stated we do in past posts, shouldn't we reduce fat consumption, which produces superoxide in order to create insulin resistance? Or is it only superoxide from glucose metabolism that is harmful and fat derived superoxide is somehow useful? Essentially, why is it healthy to have the massive superoxide produced from fat metabolism (for physiological insulin resistance) but the superoxide from a leaky, glucose-driven complex 1 is unhealthy for our mitochondria? What is it that I'm not getting here?


callingnew said...

a whole other bloody level of complexity. we are controlled by aliens. they live inside us.

Puddleg said...

@ Jack,

This is a good paper on sirtuins and NAD+, especially the concept of the NAD+ "sink".

Unknown said...

George when I saw the paper I realize you guys here would begin to see why I have been following Peter closely for 7 yrs. He and I are saying the same thing but with a different language and alphabet. This is why many of you have found my ideas so queer. I always found it remarkable because I knew from the beginning Peter and I were on the same track but how we are tackling the issues is using different core science. Peter using mitochondrial biochemistry from a biologic perspective and I was using quantum physics. For JJ andrade: watch this video I just made fo rmy next blog. IT helps you understand the issue of direction of current on the inner mitochondrial membrane and how it relates to charge separation, water chemistry, the electromagnetic force and how this is transferred to proteins in cells. The number and quality of mitochondria are directly proportional to the effects of electromagnetic force brought to bear on the mitochondrial cytochromes. 24/7 carbohydrates deliver electrons with a summer footprint to cytochrome one. These foods are designed to grow and be eaten only in long light cycles and they enter at cytochrome and give us a specific redox footprint. It turns out seasons also have their own special electromagnetic footprint that the cytochrome proteins are exquisitely designed to also sense. This is not just a food electron carbohydrate story. It is also an electromagnetic force story because of the how mitochondria are built by evolutionary design to sense the daily and seasonal changes of the light cycle and the electromagnetic spectrum and its associated forces. Water is the molecule that is the quantum communicator or the molecule fully capable of deciphering the changes and delivering that energy to the proper place in mitochondrial based upon the energies and information included in electrons from food and the sheer number of protons delivered to mitochondria.

Unknown said...
This comment has been removed by the author.
Jane said...

I suggest that it isn't glucose that's bad for mitochondria but excess calcium. Oxidative stress makes Ca go from ER to mitochondria, where it inhibits complex 1. This means more NADH and less NAD. Ca activates TCA cycle dehydrogenases, which also means more NADH and less NAD. NAD activates Sirt3, which regulates MnSOD. Too little NAD means lower MnSOD activity and too much superoxide.

Unknown said...

And Jane non native EMF causes calcium efflux in every cell in the body. Ions in any static and uniform magnetic field will typically move in a circle with a cyclotron frequency determined by its charge q, its mass m, and the strength of the magnetic field called B. The operation of a cyclotron is based on the fact that the period of the motion of a charged particle in a uniform magnetic field is independent of the velocity of the particle, as can be seen in the following mathematical derivation:

F = ma

qvB = mv2/r

Solving for r:

r = mv/qB

Now find the period, T:

T = 1/f = 2π/ω = 2πr/v = 2πmv/qBv

Since the velocities’s cancel:

T = 2πm/qB

The “Cyclotron Frequency” f (c) immediately follows and is:

F© = qB/2πm

These ion cyclotron resonance effects were extensively investigated in Blackman’s lab but elsewhere in the 1980s up until today. All laboratories who have studied these effects found that calcium cyclotron frequency directly affects calmodulin regulation of the calcium ion concentration in solution and a host of biologic functions. These are all tied to marked alterations of voltage dependent calcium channels when the field strength is above 30 Hz. To date, 23 studies have been done and repeated this finding since 1980. Anything that affects calmodulin by definition affects magnesium ion concentrations as well in a cell. All of these things directly affect the cytochromes in mitochondria. These proteins are designed to act to sense charged particles like electrons and protons and their spins and energies just like an MRI machine does. We understand the inputs to mitochondria and the outputs but biology has no clue about how mitochondria really work. The reason? It is a QED story not a biologic one. This is why an altered field is primordial to calcium and magnesium regulation. Taking more calcium or magnesium do nothing for the intracellular voltage channels. Using calcium channel blockers however can help marginally. Altering your native environmental EMF is the smartest move.

Why is Calcium ion frequency important for you to understand? Ion cyclotron resonance is a phenomenon related to the movement of ions in a magnetic field. today the Earth's magnetic field is no longer in its native form. It affects the NAD+ ratio's found in mitochondria directly. This is no longer a food story, it is an electrostatic charge story. Gilbert Ling said that in 1952 to deaf ears. This is why it is in biology's blind spot. Moreover, it links the photoelectric effect to the magnetic field that ions are in. Whatever the frequency of the electromagnetic field strength is dictates how biochemistry reactions will be altered for the better or the worse.

mark said...

@ Jack Kruse
You seem to agree with at least some views of Gilbert Ling, e.g. “…Gilbert Ling said that in 1952 to deaf ears. “ What do you think of his views (copied below from his web site) on chemiosmosis and Peter Mitchell? In PSS Nick Lane has nothing but praise for Mitchell. Thanks.

From : “ A Nobel Prize for Chemistry was awarded in 1978 to English scientist, Peter Mitchell for his "Chemiosmotic Hypothesis". To award a Nobel Prize for an (as-yet-unproven) hypothesis is unheard of. To the best of my knowledge and barring this one, no Noble Prizes has ever been given to authors of hypotheses before they had been proven valid beyond question. The Chemiosmotic Hypothesis was intended to provide a mechanism for the postulated membrane pumps. But Mitchell seemed totally ignorant of the vast amount of experimental evidence against the very existence of such membrane pumps. To what extent he was a victim of Glynn and Karlish's "cooked" review and other "cooked" reviews like it-in which all evidence against the most prominent (sodium) pump was completely left out--- I have no way of knowing. Not surprisingly, the Chemiosmotic theory soon became the target of one disproof after another. But for the reputation and credibility of the Nobel Prize as well as Peter Mitchell, these disproofs came too late. The Prize had already been awarded.”

Nick lane in PSS: “ …‘Not since Darwin has biology come up with an idea as counterintuitive as those of, say, Einstein, Heisenberg or Schrödinger.’ This idea, however, turned out to be true, and won Peter Mitchell a Nobel Prize in 1978. “

Unknown said...

Ironically Mark my blog today carries that answer:

Nick is great but he does not have it all worked out. Ling's ideas lead to Ray Damadian inventing the MRi. Not one invention is linked to Mitchell's work because it is WRONG.

Jane said...

I have tried to read Gilbert Ling and failed. I don't think his brain works properly. Gimme Nick Lane any day.

Unknown said...

And Mark I wrote this one over a year ago about Mitchell and Ling. Jane if you dont understand Ling then you must read Pollack new book, The Fourth Phase of Water. So simple a 3rd grader could get it.

Unknown said...

Sorry here is the link:

Peter said...

Jack, I put this comment up on Facebook about Pollack’s ideas. These are my problems addressed to Jake:

“Jake, yes. I have been working through Pollack's and trying to compare it in to Martin's ideas about White Non Smokers as the source of origin of the "membrane" potential. Both agree that the lipid by layer is a very late add-on, and an impediment to metabolism. Metabolism comes first, replication second, lipids last. With structured water I can see that IR produces an expanding exclusion zone with a 100-200mV boundary voltage. Remove the IR input and the zone will shrink (I would guess), allowing protons to re enter and do some sort of work, powered by the previous IR input. But I can't see how negatively charged metabolic molecules could fail to be excluded from the structured -ve charged zone. Photon dissociation of water gives hydroxyl as the negative charge, how would acetate or formate stay in, or enter, this zone? The attraction of Martin and Lane's ideas are that they provide a sustained geothermal proton gradient over very extended (geological) periods. Both camps also seem to agree on H2 as the primary energy source.”

Lane and Martin do not consider Black Smokers for origin of life ideas, these only persist for decades. White Non Smokers persist for millennia. There is a simple and highly plausible chemiosmotic scenario set out for WNS prebiotic chemistry.

No one could doubt that structured water is intrinsic to cells today. Or surrounding any protein structure. MRI scanner do, after all, work. But Lane and Martin work through the probable metabolism which precedes both RNA and proteins, step by step. Why acetyl CoA? Why pyruvate? Why methane or acetate as waste even in modern bacteria without cytochromes? These are seductive ideas and they make sense to me.


Puddleg said...

Erythrocytes (glycolysis-dependent cells) lack mitochondria and NADH is instead recycled outwards through the Plama Membrane Transpost System.
One aspect of this is that exported electrons give rise to intercellular ROS which oxidise ascorbate AA to its deoxy form DHA, when DHA enters the erythrocyte its reduction to AA regenerates another NAD+.

Other cells will export electrons to manage reductive stress, mainly if they become over-reliant on cytosolic glycolysis, i.e. OXPHOS fails for some reason.

I updated my last blog post to include this.

Unknown said...

Peter here is the other part of Pollack's work.....when the IR dissipates the EZ shrinks but as water migrates away from the smoker it get cold. Cold water is more dense and carries more O2 dissolved in it. It also begins to regrow the EZ and create more protons. This is why water is special and works best in summer and winter. It also shows you why Nick and Martin maybe wrong about atmospheric O2. Dense cold water is likely the first repository or O2 on this planet for Archea and cyanobacteria.......and then we have the amazing gas clathrate angle........You need to read Pollack New book. He covers most of these angles well and it is simple. As much as I like Nick and Martin........I do not think they are 100% spot on because of the RNA and proton issues. water chemistry only needs a hydrophilic substrate to charge do the basic life needed. It can do it at the floor and when it diffused away from the white smoker for one reason.......cold water. Remember Peter Alaskan King crab are huge because of the O2 content in cold water. Crabs in the gulf are small because of the warm water and low O2. There is massive geologic and oceanogrpahic evidence that life's O2 story did not need atmospheric O2 to thrive. Life arose from the seas after the Cambrian explosion and after every extinction event this planet has seen. This has to make you wonder why? The key co variable? Water.

Peter said...

Jack, all life around Black Smokers is oxygen based. Any consideration of prebiotic chemistry must be anaerobic. Hence another rejection of Black Smokers. White Non Smokers, even today, vent methane of non biological origin. H2 + CO2 giving H2O and CH4. No molecular O2 in the origin of life.


Jane said...

@Jack Kruse
I'm not sure the problem is that I don't understand Ling. Nobody doubts a lot of the things Ling talks about. Nobody believes any more (if they ever did) that cells are bags of water with stuff moving about randomly. But Ling says the sodium pump does not exist. If it doesn't, and isn't needed to keep sodium out of neurons, how do you get action potentials? If the sodium pump doesn't exist, how have people managed to clone it and sequence it? I expect Ling is right about cytoplasmic proteins binding potassium better than sodium, which means the sodium pump wouldn't have to work very hard. But it doesn't exist?

Unknown said...

Jane Ling brilliantly lays out where the AP comes from on page 255-56 in Life at the Cell and Below Cell level. You really need to look at what he says here and then Read Pollack's latest book on the Fourth phase of water. Much of the great info you bring here on metal ions and mitochondria dovetails with these ideas.

Unknown said...

Peter I understand your point clearly. The point I am trying to make is water chemistry at a white smoker does not need a membrane because of how the proton flows occur in columns of seawater. This is the crux of some of Pollack's work. It brings up more questions of Mitchell's work and should ask all of us to go back and look at what we all believe. I think the story on life's origin is tied to ideas other than Mitchell or Martin.

Jane said...

@Jack Kruse
If what Ling says about the action potential is so brilliant, you should be able to explain it to me in a couple of paragraphs. Short paragraphs.

Unknown said...

Now for the last Peter: When you understand the linkage of NAD+ and Sirtuin activation how does this link of the environment of mammals? Irisin. Read the Nature paper from 2012 on how they found it. IT is the hormone of how muscle talks to WAT. Why would a CAVEMEN need that when there were no Gold's Gyms 1 million years ago? One answer: Cold for shivering thermogenesis? What would fuel it? Proton uncoupling from FFA coming from White fat cells heading to newly formed BAT to burn the fat to stave off hypothermia. When it is cold is the light cycle long or short? Short. This means no photoelectric effect to grow carbs. Irisin = ketosis. This is why they are linked. The key issue for mitochondrial efficiency and capacity then becomes Ling and Pollack's idea of how the proton force would move in cold. Its the EZ from radiant energy of uncoupling. How is this all mediated? UCP1. What are UCP 1 co factors? Leptin and T3. Maybe you begin to see why my CT protocol works and why people do not see it.

Unknown said...

Cold ketosis and hydration are all linked by nature's electromagnetic spectrum. The proof is in how muscle fat and mitochondria work in that environment. Your proton series is a big part of the missing pieces.

Unknown said...

Short enough Jane?

Jane said...

Right length wrong topic

Peter said...

Hi jj,

Sorry to be so long in replying, I lost where this comment came in recent set of posts. Fat based metabolism appears to generate less superoxide under fasting conditions. This is due to FFAs uncoupling the inner mitochondrial membrane. Superoxide is essential, as a nano molar pulse, to allow insulin signalling. Uncoupled mitochondria, with a low delta psi, make the cell insulin resistant through LACK of superoxide.

Saturated FFAs drive reverse electron flow through complex I when delta psi is high by inputing electrons directly to the CoQ pool via FADH2. Under elevated glucose AND saturated fats a cell resists insulin to limit caloric intake. This is the post prandial situation. H2O2 per se is inhibiting insulin’s action.

I see metabolic problems coming from sources of glucose which do not “see” insulin resistance (fructose) or fats which do not generate adequate FADH2 input (PUFA) to allow this insulin resistance.

Research is only just starting to ask relevant questions about superoxide when the mitochondria are being run without ETC blockade, at various points to test for leaks. These leaks, when detected using inhibitors, may or may not occur under physiological conditions. From we can see that metabolism based on palmitate generates around 200pmol/m of H202 and glutamate/malate generates about the same (graphically in Fig 5 and in the text which follows). However, to get a pure NADH result you need to block the FADH2 input from succinate dehydrogenase (hence the malate) so allowing the TCA to turn might well give a higher H2O2 than palmitate. Of course palmitate, under the conditions tested, was not only inputing at electron transporting flavoprotein dehydrogenase as FADH2 but will also have been turning the TCA and inputting not only FADH2 at ETFdh but also via succinate (no malate used with palmitoyl carnitine) but also some NADH as well. i.e. the result for palmitate might well be more physiological and lower in H2O2 generation than NADH input without the malate. Seems that pamitate might be a rather nice mitochondrial fuel.

I sort of like that.


blogblog said...

The logical place for anaerobic bacteria to have first evolved is in the crust. The crustal environment is completely stable for millions of years at a time. There is an unlimited supply of nutrients and water and no harmful oxygen or ionising radiation.

See "The Deep Hot Biosphere" by Thomas Gold for more information. [Free Full Text]