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[Study] Acquired Mitochondrial Abnormalities Including Epigenetic Inhibition of Superoxide Dismutase

Discussion in 'Other Health News and Research' started by nanonug, Mar 1, 2018.

  1. nanonug

    nanonug Senior Member

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    https://www.ncbi.nlm.nih.gov/pubmed/27343087

    Abstract
    There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxidedismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α). (2) HIF-1α increases expression of pyruvate dehydrogenase kinase (PDK), which impairs oxidative metabolism and promotes a glycolytic metabolic state. (3) Mitochondrial fragmentation, partially due to mitofusin-2 downregulation, promotes proliferation. This review focuses on the recent discovery that decreased expression of SOD2, a putative tumor-suppressor gene and the major source of H2O2, results from hypermethylation of CpG islands. In cancer and PAH hypermethylation of a site in the enhancer region of intron 2 inhibits SOD2 transcription. In normal PASMC, SOD2 siRNA decreases H2O2 and activates HIF-1α. In PAH, reduced SOD2 expression decreases H2O2, reduces the cytosol and thereby activates HIF-1α. This causes a glycolytic shift in metabolism and increases the proliferation/apoptosis ratio by downregulating Kv1.5 channels, increasing cytosolic calcium, and inhibiting caspases. The DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, which restores SOD2 expression, corrects the proliferation/apoptosis imbalance in PAH and cancer cells. The specificity of PAH for lung vessels may relate to the selective upregulation of DNA methyltransferases that mediate CpG methylation in PASMC (DNA MT-1A and -3B). SOD2 augmentation inactivates HIF-1α in PAH PASMC and therapy with the SOD mimetic, MnTBAP, regresses experimental PAH. In conclusion, cancer and PAH share acquired mitochondrial abnormalities that increase proliferation and inhibit apoptosis, suggesting new therapeutic targets.
     
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  2. nanonug

    nanonug Senior Member

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    I'm adding Superoxide Dismutase (GliSODin) to my protocol stack. Hopefully, the gliadin in GliSODin won't kill me.
     
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  3. ljimbo423

    ljimbo423 Senior Member

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    From the reading I've done SOD is a very crucial antioxidant. Hope you get some relief from it, maybe a lot.:thumbsup:

    I just recently went up from 100 to 200mg a day of coq10, about a week ago.

    I have noticed a big increase in energy, that is continuing. I was taking 400mg a day last summer but didn't have this big increase in energy. I guess timing is everything!:)

    Jim
     
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  4. Learner1

    Learner1 Forum Support Assistant

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    Thanks for posting the above study. I'm very interested in increasing SOD.

    GliSODin is made from cantaloupe extract bound to wheat gluten..not good for people with gluten sensitivity.

    From what I could gather, it works to replace either SOD1 or SOD3, not SOD2, which is the mitochondrial SOD. Several sources say if you replace it, it can stop your own production.

    This discussion brings up food for thought and links to some studies:

    http://www.longecity.org/forum/topic/51599-beware-of-glisodin/

    Joseph overcast Selfhacked says this about increasing SOD2:

    https://www.selfhacked.com/blog/the...r-sod2/#Top_Fixes_if_You_Have_Low_SOD2_Levels

    One thing you might check is your manganese level, as it is needed for Mn-SOD.

    Finally, a big issue with being short of SOD2cis damage to mitochondrial membranes, which can impact the efficiency of ATP production, especially if you are prone to peroxynitrite production.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964747/

    If this is going on, replenishing lipids to assist membranes may be helpful. I take a product called NT Factor to help with this.

    https://www.sciencedirect.com/science/article/pii/S0005273613004070
     
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  5. percyval577

    percyval577 Senior Member

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    Maybe because it´s winter now (higher melatonine).
     
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  6. nanonug

    nanonug Senior Member

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    Thank you for all the info.

    Let me briefly explain my rationale for taking GliSODin: the hypothesis I am working with is that my hypometabolic state is due to decreased activity of pyruvate dehydrogenase complex due to excessive ROS, in particular superoxide. Also, as part of this hypothesis, is my inability to produce enough SOD to scavenge excessive ROS.

    Very true. That's why I said "hopefully, the gliadin in GliSODin won't kill me". I've tested negative for Celiac and I have no reason to believe I am sensitive to gluten. Gluten is also used as a delivery mechanism in many prescriptions medications.
    The fact that Mn-SOD is the one produced in the mitochondrion (via the SOD2 gene) doesn't mean that Cu-Zn-SOD (via either SOD1 or SOD3) won't "attack" superoxide produced as part of the electron transport chain operation - the superoxide molecule is always the same, O2-. The question is whether the exogenous SOD will be able to get to this superoxide "in time." I don't have an answer to this question. This, however, won't prevent exogenous SOD from dealing with the superoxide associated with an overactive immune system.

    The only "credible source" I could find is this study: "Blood Superoxide Dismutase (SOD) Following Oral Administration of Plant SOD to Healthy Subjects." Note my emphasis on "Healthy Subjects" given my hypothesis of reduced SOD production deficiency. I don't think the conclusion in the study applies to me as I'm not a "healthy subject." The individual on LongeCity talking about his experience with burning under the sun after 1 hour of exposure following discontinuation of GliSODin is lucky; I've always burned under the sun in less than 15 minutes, thus "justifying" my hypothesis.

    The only thing I found useful in the SelfHacked link was the suggestion of using ubiquinone as a reducing agent for superoxide produced in the electron transport chain. I already supplement with ubiquinone (in addition to ubiquinol.)

    I already supplement with manganese, copper and zinc.

    True, but without excessive superoxide there won't be much peroxynitrite production as peroxynitrite is produced in vivo by the reaction of superoxide with nitric oxide.

    Thanks, I'll look into this.
     
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  7. percyval577

    percyval577 Senior Member

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    The answer to (1) should be "no".
    If I am rembering right - and I am to exhausted to refind the sources. My remembering: On the very enviroment of the mitochondria membrane there is only Mn-SOD able to scavange molecules with reactive O-molecules (reactive oxygene species ROS). Therefore, without or to less Mn-SOD, these molecules will do something not normal, and only these-ones who manage to escape from any not-normal reaction nearby the mitochondria membrane can be scavanged by the other two SOD´s (copper or zinc supeoxidedismutase).
    But - here is only my rembering (or even my own good experience?? but I doubt to have any loss of Mn-SOD) - they would do not much harm (at least if you not suffering from very special dysfunction in respect of mitochondria): I want to refind the source, which is maybe ten years old, that said, people without Mn-SOD = SOD2 tend to get a faty liver during their life. I am sorry for being "so lazy".

    (2) Here I would be careful (and from my experience: very careful), not always means the more, the better! For sure, with more manganese you should increase your Mn-SOD, what seems to be good.
    On the other hand, and now here doesn´t come a direct path but a indirect one: With more manganese you will produce more nitric oxide ... (I quoted the literature in my thread on manganese)
    And this then yields reactive nitrigene species (RNS) including peroxynitrite, bad for mitochondria as well ... and in the same manner bad: bad for their membranes.
    Now you have the choice:
    you can try (a) to diminish the O-molecules and to elevate the N-molecules (by elevating manganese)
    or you can try (b) to elevate the O-molecules and to diminish the N-molecules (by lowering manganese).

    What do you want to? The further question: What could already be about to happen in your body? My guess: (a) Therefore I would not increase manganese (and I myself even look to lower it).
    Furthermore I would guess, having this choice in view of our body is not an evolutionary accident, but has evolved during long long times to "restrict" these mitochondria - as well as there must be a lot of mechanisms to ensure these internal procaryotics. Our complex body shoud not be of stone, but al things are about to move, here more there less and so on (and here something goes wrong with us I suppose).

    Of course I have to admit peroxynitrite ONOO in special looks more potent from oxygene containing three instead of only one nitrigene. But who knows the whole story, and I have my experience leading to feeling myself healthy. And indeed there should be much much more O-molecule flying around in our body than N molecules coming from NO, what is only produced by three special synthases (especially or as far as known well enough).

    Best Greetings
     
    Last edited: Mar 2, 2018
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  8. nanonug

    nanonug Senior Member

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    Might very well be the case. In this paper, "Topology of Superoxide Production from Different Sites in the Mitochondrial Electron Transport Chain", it is argued however, that mitochondria are not a big producer of ROS unless they are burning fatty acids. From the paper: "Mitochondria did not release measurable amounts of superoxide or hydrogen peroxide when respiring on complex I or complex II substrates. Mitochondria from skeletal muscle or heart generated significant amounts of superoxide from complex I when respiring on palmitoyl carnitine." This study was done with rats and pigeons, by the way, so whether this applies to humans is not clear.

    No need to be sorry, happens to me all the time as well.

    Wasn't aware of this, thanks for pointing it out. I'll look into this further although I'm supplementing at or close to RDA levels so I suspect it shouldn't be a problem.
     
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  9. nanonug

    nanonug Senior Member

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    This study, entitled "Complex I generated, mitochondrial matrix-directed superoxide is released from the mitochondria through voltage dependent anion channels", argues that mitochondria do indeed release superoxide to the cytosol, after which it is subjected to transformation by Cu-Zn-SOD. At least in mice!

    Abstract
    Mitochondrial complex I has previously been shown to release superoxide exclusively towards the mitochondrial matrix, whereas complex III releases superoxide to both the matrix and the cytosol. Superoxide produced at complex III has been shown to exit the mitochondria through voltage dependent anion channels (VDAC). To test whether complex I-derived, mitochondrial matrix-directed superoxide can be released to the cytosol, we measured superoxide generation in mitochondria isolated from wild type and from mice genetically altered to be deficient in MnSOD activity (TnIFastCreSod2(fl/fl)). Under experimental conditions that produce superoxide primarily by complex I (glutamate/malate plus rotenone, GM+R), MnSOD-deficient mitochondria release ∼4-fold more superoxide than mitochondria isolated from wild type mice. Exogenous CuZnSOD completely abolished the EPR-derived GM+R signal in mitochondria isolated from both genotypes, evidence that confirms mitochondrial superoxide release. Addition of the VDAC inhibitor DIDS significantly reduced mitochondrial superoxide release (∼75%) in mitochondria from either genotype respiring on GM+R. Conversely, inhibition of potential inner membrane sites of superoxide exit, including the matrix face of the mitochondrial permeability transition pore and the inner membrane anion channel did not reduce mitochondrial superoxide release in the presence of GM+R in mitochondria isolated from either genotype. These data support the concept that complex I-derived mitochondrial superoxide release does indeed occur and that the majority of this release occurs through VDACs.
     
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  10. Learner1

    Learner1 Forum Support Assistant

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    I had a mitochondrial function test done which showed very low Complex I activity but very high a complex IV activity, which is cranking out huge amounts of ROS. They told me 15 out of 20 ME/CFS patients had a similar pattern. I'm waiting on more info about this process and will post as I get it.

    In the meantime, my doctor had me get some NO test strips from Humann on Amazon. Turns out I am LOW in NO, not high, and I have a lot of symptoms of low NO. Pall says we have high NO, but Dave Whitlock talks about low NO.

    But, we also suspect I have high Peroxynitrites and that the Complex IV superoxide radicals are driving them. Maybe the NO is being used up? We are testing nitrotyrosine to check.

    As for the SOD, the conversion of superoxide to ONOO- is very quick, so you need the SOD2 to be there. I'm homozygous for all the SOD2 SNPs and tend to run short in Mn, so my doctor thinks I "have a broken SOD system".

    All of this is happening with significant supplementation of all of Pall's supplements. I'm trying to figure out how to reduce the Complex IV overactivity and superoxide production. From what I gather, and I am getting more on this, supporting Complex I so it works better, should calm Complex IV down. I'm not sure why yet, but will find out.

    In the meantime, my doctor had me testing NO pre- and post- exertion, then supplementing ornithine, citrulline, and glutathione if I feel fatigued.

    As I've felt better with other interventions, I've been doing more, but hitting a wall..I'm suspecting its an increase in oxidative and nitrosative stress generated by my mitochondria as my body demands energy.
     
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  11. Sushi

    Sushi Moderation Resource Albuquerque

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    Have you read about Dr. Julian Stewart's work with NO in POTS patients?
     
  12. Learner1

    Learner1 Forum Support Assistant

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    No, can you point me to something? I found this but though it mentions NO, I don't see anything useful....

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511479/

    My variant is high blood pressure and seems to be caused by adrenergic antibodies, though I'm sure some biochemistry is involved...and low NO seems to correlate with high BP.
     
  13. Sushi

    Sushi Moderation Resource Albuquerque

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    I've just been aware of Dr. Stewart for many years though dysautonomia boards, but I can't point you to anything written other than what can be found on our friend Google.
     
  14. Learner1

    Learner1 Forum Support Assistant

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    I found a mention of Stewart's clinical trial, which says:

    "We hypothesize that impairment occurs because of excessive production of nitric oxide (NO) which reduces the ability of the nerves to produce vasoconstriction."

    This is confusing to me. I have low NO, not high. And my POTS seems to be autoimmune, caused by adrenergic antibodies.

    And, though the POTS is mighty inconvenient, the issue of mitochondria not functioning properly and generating superoxide and ONOO- can be very damaging long term, causing cancer, Parkinson's, etc. It's at a more essential (deeper) level in the body. The mito dysfunction impacts ATP production and causes fatigue and PEM.

    But there are likely interrelationships.
     
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  15. sb4

    sb4 Senior Member

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    Have you read Peter@Hyperlipids series on protons? It is very interesting. He explains the increase in superoxide at cytochrome 1 as a signaling molecule that informs the cell of energy status and how insulin sensitive it needs to be.

    Basically fats have high FADH2 / NADH ratio input to mitochondria and carbs have low ratio. The ratio determines how likely ubiquinone is likely to get "clogged up". If you are feeding half electrons through Cyt2 and half through Cyt1 then quite often the electron getting fed through cytc1 won't be able to jump to ubiquinone because it will already be occupied by the electron from Cytc2; so it will hop backwards (reverse electron flow) through Cyt1 down a differen't path that generates superoxide.

    So a very high fat meal will generate lots of superoxide and very high carb will generate very little (as ubiquinone won't be getting backed up from electrons from Cytc2 as there is very little input there from high carb).

    This superoxide is used to signal insulin sensitivity. If you have low glucose levels in the blood, due to high fat or fasting, you don't wan't fat cells to be insulin sensitive and pulling in sugar preventing the organs that actually need it like the brain from getting the proper amount. Whereas if you've just eat a high carb meal, you will want your fat cells to be very insulin sensitive so that they can take some of that high level of glucose out of the blood. So the superoxide is low which signals the cell to keep insulin sensitivity high.

    My point is, we need to keep this in mind when altering our superoxide levels. Superoxide from Cyt1 is an important signaling molecule. That produced at Cytc4 I have no idea about. But maybe a supplement that doesn't mess with SOD2 could be good in this regard?
     
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  16. Learner1

    Learner1 Forum Support Assistant

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    Ok, but oxidative stress is the one thing the clinicians agreed on at the recent summit.

    From my recent test it seems I'm generating lots of superoxide, not in Complex I, but further along in the ETC. My SOD production is a problem, as are peroxynitrites. My NutrEval consistently shows high lipid peroxides, low glutathione, ALA, A, C, E, and plant based antioxidants, even eating plenty of vegetables and significant supplementation. B vitamins are consistently low, too, especially folate and B12, even with massive supplementation.

    What is all this superoxide I'm making signalling? It seems wise to calm it down, but there's so little info out there on doing so.
     
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  17. sb4

    sb4 Senior Member

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    @Leaner1 First off I will say I don't know if reducing oxidative stress is a good idea or a bad idea. I would guess that in a CFS patient who is producing lots chronically, lowering it could be a good thing to get the body "back in balance". What I mean is that it could well be that acute inflammation is necessary and good, yet chronic creates a vicious circle which needs to be broke out of.

    Yet I have come across the idea that inflammation isn't bad several times now from several different sources. The reverse electron flow superoxide generation seems to be very important in insulin signalling and energy status signalling. ROS seem to be essential for the immune system to fight pathogens.

    Robert O'Becker showed that inflammation at an injury site was a signal to direct healing efforts to that area. [Brain + spine = positive charge, extremeties negative charge. Cut off salamanda leg and the wound becomes positively charged (inflammation) which directs stem cells/nutrients/immune/etc to that area; limb regenerates. If you get rid of inflammation / positive charge in this area, limb does not regenerate.]

    I am also listening to a chris masterjohn podcast right now were he is "ranting" about how antiinflammatories aren't necessarily good and interfere with signaling.

    I think our best bet is trying to support the body in what it's doing. If glutathione or sod are overwhelmed then do things to support them as this will probably lead to excess oxidation than is needed for signaling and cause damage.

    I think maybe we are producing all this inflammatory signalling because of an underlying chronic infection but I really have no idea. I intend to try certain anti inflammatory agents etc, and see if I feel better or not. This is better than relying too much on theories I guess.
     
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  18. percyval577

    percyval577 Senior Member

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    You might be interested in the following recapture, including ADP and misleading electrons [my translation, and I am still lazy... ]
    "Oxidativer Stress - ein Risikofaktor für mitochondriale Deletionen." (internet title I think); Franziska Weber:
    "Die Rolle von oxidativem Stress bei der Entstehung von Deletionen der mitochondrialen DNA ..." diss 2011.

    "1.322 ... The reduction O2 -> H2O is bound to the phosphorylation of ADP via DeltaPsi [ie electric gradient]. When the exogenous level of ADP is huge, the ATP synthase is driven by complex V, DeltaPsi is becoming wider and O2 is used for the purpose to rebuild DeltaPsi (state III-respiratory). When the level of ADP is a restriction, DeltaPsi is becoming less, ETC slows down, and O2 is used only low (state IV-respiratory). The ratio III : IV is called respiratory control ratio (RCR) (Kokosza JE, 2001).
    0.4-4% of the moelcular O2 used up by mt is resulting in a toxic byreaction: Out of the initial steps of the ETC the high toxic {´O2-} is built instead of H2O via a transfer of a single electron. The main source of such electrons, which are building {´O2-}, is complex I (Chance B 79, Turrens JF 85, Murphy MP 09). The SOD2 makes {´O2-} becoming H2O2. The mitochondrial H2O2 is then reduced to H2O by the Gluthationperoxidase-1 (Gpx-1). But in appearance of reduced transition metals the H2O2 can get converted to high toxic {´OH} via the Fenton-reaction (Giulivi C 95). When the OXPHOS is hemmed the rate of mischieving electrons elevates and therefore ROS. That means, in the passiv [?] state (=IV) the ROS production is higher than in the activated state (=III)."


    The next sentences in short: too high for detox capacitiy -> swollen mt -> cytochrome c gets into the plasma -> apoptosis.
    The goal of the diss was to show a causing effect on aging, but couldn´t pro nor con.
    Learner1, you might be interested in the overview on page 32, guessing should not be difficult mostly.
     
    Last edited: Apr 17, 2018
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  19. ljimbo423

    ljimbo423 Senior Member

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    I apologize right up front for bringing up something you might consider a closed issue. It looks like LPS can cause an increase in iNOS, peroxynitrite and superoxide-

    LINK

    If you do have higher than normal levels of LPS, that could explain the high ROS levels and why the massive doses of antioxidants you are taking can't bring them down. Because the cause is still there, to some degree, constantly creating more ROS? A possibility maybe?


    Jim
     
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  20. nanonug

    nanonug Senior Member

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    No, I haven't but seems to be an interesting idea. I remember reading somewhere (some published study) that most ROS is produced when Complex I is working in "reverse" but that no one was quite certain under which conditions it happened or why.

    It's definitely a good point. My current GliSODin bottle is almost empty and I may decide to stop using, at least for a while, to see what happens.
     
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