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Manipulating mitochondrial dynamics

nad nad+ c60 mito fission fusion stearic acid mtdna methylene blue

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#781 Nate-2004

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Posted 30 January 2018 - 07:18 PM

Nate

Read the cell.com article above. Ribose enabled Nicotinamide to enter cell. No Riboside no NAD

 

Attaching full text, where did you read that part? I only see mention of ADP Ribose three times and one mention of it as ribose-1-phosphate.

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#782 Nate-2004

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Posted 01 February 2018 - 04:20 PM

Apigenin is better absorbed when combined with flaxseed.

 

https://www.ncbi.nlm...les/PMC3850025/

 

This is great since I was already putting ground flaxseed in my celery and parsley smoothies.



#783 Nate-2004

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Posted 05 February 2018 - 03:40 PM

I can't see this whole article but I'm trying to find out what effects the sauna might have on mitochondria, especially QC. Only thing I've found so far.

 

 

Heat stress induces mitochondrial adaptations in skeletal muscle

 

 

 

also this:

 

Hsp78 chaperone functions in restoration of mitochondrial network following heat stress

 


Edited by Nate-2004, 05 February 2018 - 03:44 PM.

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#784 Female Scientist

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Posted 06 February 2018 - 06:29 PM

effects the sauna might have on mitochondria, especially QC. Only thing I've found so far.


Heat stress induces mitochondrial adaptations in skeletal muscle

Nate, I’m curious too. We have been experimenting with an at-home InfraRed sauna, with good effect. Lots of good research on Red Light therapies....seems to impact mitochondria....not sure if it’s good for fusion, fission, or both??
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#785 Nate-2004

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Posted 06 February 2018 - 06:40 PM

I know most of the studies on heat acclimation, sauna use and heat stress involved temperatures above 80c. I wish they'd do more study on the lower temperature infrared saunas.


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#786 Nate-2004

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Posted 07 February 2018 - 06:52 PM

After looking into how to avoid stearic acid I'm coming up with very few options as far as meals go. One of the easiest of options is rice and beans, and apples, but keep in mind that beans have leucine, 334mg every 100g. Apples are incredibly satiating and are probably the best bang for your buck when it comes to fission days.

 



#787 Turnbuckle

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Posted 08 February 2018 - 01:52 PM

An experiment with the morning fission protocol of post 714 + 2g each of nicotinamide and ribose, and with an added 4 caps of parsley extract (Nature's Way, 450 mg) produced a gym performance more akin to fusion than fission, so apparently other components of parsley interfere with fission. Thus it appears that parsley or parsley extract cannot be substituted for apigenin.


Edited by Turnbuckle, 08 February 2018 - 01:59 PM.

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#788 Ovidus

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Posted 10 February 2018 - 06:42 PM

Hi Everyone,

 

I have just started a thread here:

http://www.longecity...of-nr/?p=840666

which I think is very relevant for the posters in this thread. Turnbuckle has already kindly posted there -thanks a lot Good Sir...

 

I am basically speaking of the negative effects NR, as well as N+R, had on me, but also mention the very positive effects it had. The bottom line IMO is that NR (or N+R) is a very potent substance. One unintended influence of this thread was that people have come to think of NR as almost exclusively manipulating mitochondrial dynamics and doing little else. I am trying to point out in the linked thread above that NR does just an immensely broad spectrum of things and anything that has such wide-ranging and such strong effects cannot be all good. It has to have a bad side too.

 

I would tremendously appreciate your input on the above thread and hope that it can also help some posters here see NR in a differnet and broader light.

 

Thanks a lot 


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#789 Turnbuckle

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Posted 10 February 2018 - 07:41 PM

Hi Everyone,

 

I have just started a thread here:

http://www.longecity...of-nr/?p=840666

which I think is very relevant for the posters in this thread. Turnbuckle has already kindly posted there -thanks a lot Good Sir...

 

I am basically speaking of the negative effects NR, as well as N+R, had on me, but also mention the very positive effects it had. The bottom line IMO is that NR (or N+R) is a very potent substance. One unintended influence of this thread was that people have come to think of NR as almost exclusively manipulating mitochondrial dynamics and doing little else. I am trying to point out in the linked thread above that NR does just an immensely broad spectrum of things and anything that has such wide-ranging and such strong effects cannot be all good. It has to have a bad side too.

 

I would tremendously appreciate your input on the above thread and hope that it can also help some posters here see NR in a differnet and broader light.

 

Thanks a lot 

 

 

N+R increases the ATP output, and that is the first reason to take it. However, taking large amounts of N+R (or NR or NMN) continuously could have negative results if it puts you into a continuous state of fission (driven by high NAD+/NADH) or if you develop a population of mitochondria dependent on it. So better to cycle through fission and fusion as the body does naturally, but with greater swings as with age the natural fission & fusion process becomes muted and difficult-to-clear zombie mitochondria can appear. So driving fission and fusion with supplements (including N+R) clears out defective mitochondria and pushes the mito population to a more youthful state, even while you get the advantage of increased ATP output.


Edited by Turnbuckle, 10 February 2018 - 07:42 PM.

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#790 Empiricus

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Posted 11 February 2018 - 07:41 AM

I noticed the new topic, "Dark Side of NR" has been locked.  I guess somebody doesn't want us talking about the dark side.  I was just going to say that my major complaint on NR, sore feet, went away eventually.   I still think it's interesting that NR has a range of positive effects I never felt experimenting with N+R.  



#791 Turnbuckle

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Posted 11 February 2018 - 10:24 AM

I noticed the new topic, "Dark Side of NR" has been locked.  I guess somebody doesn't want us talking about the dark side.  I was just going to say that my major complaint on NR, sore feet, went away eventually.   I still think it's interesting that NR has a range of positive effects I never felt experimenting with N+R.  

 

 

Doesn't look locked to me. As for NR vs N+R, I never got anything from NR compared to using this protocol, so each to his own, I suppose. I would suggest, however, that you try the high energy protocol in post #746.  


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#792 Ovidus

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Posted 11 February 2018 - 03:17 PM

 

Hi Everyone,

 

I have just started a thread here:

http://www.longecity...of-nr/?p=840666

which I think is very relevant for the posters in this thread. Turnbuckle has already kindly posted there -thanks a lot Good Sir...

 

I am basically speaking of the negative effects NR, as well as N+R, had on me, but also mention the very positive effects it had. The bottom line IMO is that NR (or N+R) is a very potent substance. One unintended influence of this thread was that people have come to think of NR as almost exclusively manipulating mitochondrial dynamics and doing little else. I am trying to point out in the linked thread above that NR does just an immensely broad spectrum of things and anything that has such wide-ranging and such strong effects cannot be all good. It has to have a bad side too.

 

I would tremendously appreciate your input on the above thread and hope that it can also help some posters here see NR in a differnet and broader light.

 

Thanks a lot 

 

 

N+R increases the ATP output, and that is the first reason to take it. However, taking large amounts of N+R (or NR or NMN) continuously could have negative results if it puts you into a continuous state of fission (driven by high NAD+/NADH) or if you develop a population of mitochondria dependent on it. So better to cycle through fission and fusion as the body does naturally, but with greater swings as with age the natural fission & fusion process becomes muted and difficult-to-clear zombie mitochondria can appear. So driving fission and fusion with supplements (including N+R) clears out defective mitochondria and pushes the mito population to a more youthful state, even while you get the advantage of increased ATP output.

 

 

These are very valid points which you have made earlier during this thread and your contributions are very valuable. But we are making the same mistake one more time: 
We are reducing NR (or N+R) only to its effects on mitochondria and almost assuming that it does nothing else -and that every effect of NR can be explained through its impact on mitochondria. That is the very approach that I respectfully disagree with. 


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#793 Turnbuckle

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Posted 11 February 2018 - 04:02 PM

 

 


 

 

These are very valid points which you have made earlier during this thread and your contributions are very valuable. But we are making the same mistake one more time: 
We are reducing NR (or N+R) only to its effects on mitochondria and almost assuming that it does nothing else -and that every effect of NR can be explained through its impact on mitochondria. That is the very approach that I respectfully disagree with. 

 

 

 

ATP is the energy currency of the cell. Boosting ATP for several days as in post 746 will produce a healthier cell, and healthier cells will produce healthier organs, and in turn a healthier organism. Thus the starting point should be with creating a healthy population of mitochondria, as that will maximize ATP production and minimize ROS. If you don’t agree with that, you need to explain yourself. Certainly NAD is used for other purposes in the cell, but I don't see how that can be unwound from ATP production.


Edited by Turnbuckle, 11 February 2018 - 04:31 PM.

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#794 Empiricus

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Posted 13 February 2018 - 06:52 PM

Thanks, Turnbuckle, I will try #746 once I track down food grade stearic.  I'm not sure substitution with dark chocolate is working.  (Unfortunately, Amazon isn't an option for me).

 

I have a question: 250 mg of NR (usually that's 2 capsules) would be same as how many mg of niacinamide and how many of riboside, if both are taken separately?   For some reason, I find NR easier to tolerate than N+R, but that could be that I don't take equivalent doses. 

 

The positive things I notice with NR are improved mental sharpness and less fatigued appearance, both lasting for a number of hours.  But results vary by bottle, some don't bottles don't seem to do anything for me.  These are things I haven't yet observed experimenting with N+R.  Of course, the protocol is intended to provoke more lasting improvements than the sort-term benefits I'm reporting with NR.  


Edited by Empiricus, 13 February 2018 - 07:04 PM.


#795 Turnbuckle

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Posted 13 February 2018 - 06:58 PM

Thanks, Turnbuckle, I will try #746 once I track down food grade stearic.  I'm not sure substitution with dark chocolate is working.  (Unfortunately, Amazon isn't an option for me).

 

I have a question: 250 mg of NR (usually that's 2 capsules) would be same as how many mg of niacinamide and how many of riboside, if both are taken separately?   For some reason, I find NR easier to tolerate than N+R, but that could be that I don't take equivalent doses. 

 

The positive things I notice with NR are improved mental sharpness and less fatigued appearance, both lasting for a number of hours.  These are things I haven't yet seen with N+R.    

 

250 mg NR is the rough equivalent of 125 mg each of N and R.


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#796 Empiricus

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Posted 13 February 2018 - 07:09 PM

To think it takes 4 capsules of expensive NR to get as much N as in one standard 500 mg capsule of dirt cheap niacinamide!  


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#797 Nate-2004

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Posted 13 February 2018 - 07:49 PM

You don't really need to buy food grade stearic acid. Here's a list of all the foods that stearic acid is in. Starting with 14g per 100g.  I actually have a harder problem with getting it out of my diet for fission days. It's ridiculously hard to achieve and maintain for 3 days in a row. It's almost impossible to achieve on a ketogenic diet.  

 

The cream I love in my coffee is 5 grams of stearic acid per cup. It's insane, and that's before I even eat food. You're still going to get a few milligrams unless you take your coffee black and don't eat for 3 days straight. Then, maybe and only then, will you get rid of stearic acid completely. A 5 day water fast will probably do the trick for sure. Good luck. I can never make it past the second or third day.


Edited by Nate-2004, 13 February 2018 - 07:57 PM.

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#798 Empiricus

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Posted 13 February 2018 - 09:19 PM

You don't really need to buy food grade stearic acid. Here's a list of all the foods that stearic acid is in. Starting with 14g per 100g.  I actually have a harder problem with getting it out of my diet for fission days. It's ridiculously hard to achieve and maintain for 3 days in a row. It's almost impossible to achieve on a ketogenic diet.  

 

The cream I love in my coffee is 5 grams of stearic acid per cup. It's insane, and that's before I even eat food. You're still going to get a few milligrams unless you take your coffee black and don't eat for 3 days straight. Then, maybe and only then, will you get rid of stearic acid completely. A 5 day water fast will probably do the trick for sure. Good luck. I can never make it past the second or third day.

 

I just started a keto diet.  What about consuming a lot of coconut oil on the fission days?  100g is 862 cal = 2.6g of stearic  (vs butter 7.3g and 717 cals, cream 7 g and 345 cal).  So looked at by calorie (not just quantity),  coconut oil looks like a possible option.  https://wholefoodcat...s_and_oils/low/ Any better ideas?  


Edited by Empiricus, 13 February 2018 - 09:30 PM.

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#799 Nate-2004

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Posted 13 February 2018 - 10:41 PM

If you consume a lot of coconut oil you're going to get a lot more than just 2.6g of stearic. Just 6 tablespoons of that is 2.6g I think, most people put two in their coffee. If you want to still eat and just minimize it, look at the last page of that link and work your way the other direction. Spinach, Grapes, Apples, Rice, mostly carbs. If you're on keto now, then your best bet is just spinach, kale, blueberries (no more than 50g), a tomato, squeezed lemon, parsley, celery, all ground up in a smoothie with some water. Net carbs in that are pretty low, 5 to 10g max. You're stuck with that man. Not fun. Like I said, nearly impossible. I'd hate it if all I could eat was that smoothie. You could add MCT oil though, it's just caprylic acid mostly and decanoic acid otherwise. It's not stearic at all, but not entirely sure if that doesn't also have fusion inducing properties.

 

I honestly don't know what the minimum amount of stearic acid is to induce fusion, but I'd assume any amount would. The half-life is 17 hrs. That means if you get 15g, you still have 7g left 17 hrs later and 3g left 17 hrs after that.


Edited by Nate-2004, 13 February 2018 - 10:42 PM.

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#800 BieraK

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Posted 13 February 2018 - 11:52 PM

Just a bit speculative
 

 

First, HIF-1 activates the gene encoding pyruvate dehydrogenase (PDH) kinase 1 (PDK1), which phosphorylates and inactivates the catalytic subunit of PDH, the enzyme that converts pyruvate to acetyl coenzyme A (AcCoA) for entry into the mitochondrial tricarboxylic acid (TCA) cycle [25]. Second, HIF-1 activates the gene encoding BNIP3, a member of the Bcl-2 family of mitochondrial proteins, which triggers selective mitochondrial autophagy [26]. Interference with the induction of either of these proteins in hypoxic cells results in increased ROS production and increased cell death

https://www.scienced...167488910002223

 

So if I'm reading this in the right way, HIF-1a activates BNIP3 and thus leads to mitochondrial autophagy.... Well there is a very well known russian molecule which main mechanism of action is HIF-1a activation: Noopept

 

Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept

 

Spoiler

https://www.ncbi.nlm...les/PMC4837574/


Edited by BieraK, 13 February 2018 - 11:53 PM.

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#801 Empiricus

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Posted 15 February 2018 - 01:01 AM

Nate, interesting thoughts on how one might go about keto-fission.  It would be interesting to know the threshold for stearic bellow which it doesn't induce much fusion.  Maybe we don't need to worry so much if 5g is bare minimum.  

 

Turnbuckle, in post #746 you stated that you were taking 5g of stearic.  Do higher amounts not make it go even better?  Does 5g seem to be close to the minimal needed or do you sense it's more than enough?

 


Edited by Empiricus, 15 February 2018 - 01:07 AM.


#802 Turnbuckle

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Posted 15 February 2018 - 03:46 AM

Nate, interesting thoughts on how one might go about keto-fission.  It would be interesting to know the threshold for stearic bellow which it doesn't induce much fusion.  Maybe we don't need to worry so much if 5g is bare minimum.  

 

Turnbuckle, in post #746 you stated that you were taking 5g of stearic.  Do higher amounts not make it go even better?  Does 5g seem to be close to the minimal needed or do you sense it's more than enough?

 

It worked for me for fusion, but for the reverse protocol where I combined N+R with fusion, 5 g of stearic seemed to wear off after about 6 hours and then if felt more like fission. More stearic acid might be needed in that case, and more might be needed on an individual basis. Everything I'm reporting is for myself, and obviously results for others may vary.


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#803 Nate-2004

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Posted 15 February 2018 - 04:58 PM

Turnbuckle, there's a quote here that I'm wondering about in terms of this fission based means of quality control:

 

https://www.fightagi...-to-damage-you/

 

This is an old 2007 post from FA but here's the confusing part to me:

 


  • Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers.

     

     

  • The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it's old, leaky, inefficient and needs to be replaced with a shiny new power plant.

     

     

  • BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

     

     

  • One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.

 

Does fission help this process by reducing the membrane potential after OXPHOS has stopped?

 



#804 Turnbuckle

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Posted 15 February 2018 - 06:12 PM

The thinking on how this works is rapidly changing. Most recently it appears to be a matter of mito size and surface depolarization.

 

First there must be fission to get the size down and to isolate loops of mtDNA (since healthy loops cover for unhealthy ones by providing sufficient proteins)--

 

 

Using a photo-labeling approach, Twig et al. (2008) found that mitochondria went through constant cycles of fusion and fission, and fission events generated two subsets of daughter mitochondria with either increased or decreased membrane potential. They further found that the daughter mitochondria with higher membrane potential would proceed to fusion, whereas the depolarized daughter mitochondria were unable to proceed to the fusion process and were removed by mitophagy. Overexpression of OPA1 led to increased mitochondria fusion and decreased mitophagy. Therefore, it seems that mitochondrial fission is essential for mitophagy.

 

 
 
If mitochondria cease to maintain surface polarization, they pick up proteins called PINK1. These are degraded by healthy mitochondria but not by defective ones. PINK1 then brings in another protein called parkin The presence of sufficient parkin is the signal for a lysosome to engulf a mitochondrion and digest it, but of course it has to be small enough to fit into the lysosome to begin with.
 

When a mitochondrion becomes uncoupled, protein import to the inner mitochondrial membrane is prevented so PINK1 is diverted from PARL and accumulates on the outer mitochondrial membrane. This yields a sensor of mitochondrial damage that can flag an individual impaired mitochondrion in a milieu of healthy ones. PINK1 on a damaged mitochondrion, through its kinase activity, recruits the E3 ligase Parkin from the cytosol specifically to that impaired mitochondrion (Fig. 3). Once there, Parkin ubiquitinates outer mitochondrial membrane proteins and induces autophagic elimination of the flagged mitochondrion (21). 
 

 

 

Giant zombie mitochondria can build up when the normal fission/fusion process of the cell is not sufficient to divide them up. Thus one purpose of the protocol is to push fission to a greater degree than normally occurs. 
 

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#805 Nate-2004

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Posted 15 February 2018 - 06:55 PM

That provides a much clearer picture. Makes sense that the theory has been refined and revised quite a bit as they continue their study. 

 

 

 

 

Nate, interesting thoughts on how one might go about keto-fission.  It would be interesting to know the threshold for stearic bellow which it doesn't induce much fusion.  Maybe we don't need to worry so much if 5g is bare minimum.  

 

You could be right there. Lately I've not been doing the protocol of 3 days fission 4 days fusion but rather a time restricted feeding (no cream in my coffee) of 14:00 to 19:00, combined with NR (250mg morning) and NAM+R (1500mg) an hour before gym and then a functional workout involving mostly resistance training via calisthenics ending with a sled push burn.

 

Then a few hours later in the day when I get home from work, I'll take 6 broccomax with my kale smoothie.  So I'm not entirely stearic acid free in this case but hopefully I'm driving up fission enough despite this. It all depends on how fast this happens.


Edited by Nate-2004, 15 February 2018 - 07:06 PM.


#806 mitomutant

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Posted 15 February 2018 - 07:04 PM

 

The thinking on how this works is rapidly changing. Most recently it appears to be a matter of mito size and surface depolarization.

 

First there must be fission to get the size down and to isolate loops of mtDNA (since healthy loops cover for unhealthy ones by providing sufficient proteins)--

 

 

Using a photo-labeling approach, Twig et al. (2008) found that mitochondria went through constant cycles of fusion and fission, and fission events generated two subsets of daughter mitochondria with either increased or decreased membrane potential. They further found that the daughter mitochondria with higher membrane potential would proceed to fusion, whereas the depolarized daughter mitochondria were unable to proceed to the fusion process and were removed by mitophagy. Overexpression of OPA1 led to increased mitochondria fusion and decreased mitophagy. Therefore, it seems that mitochondrial fission is essential for mitophagy.

 

 
 
If mitochondria cease to maintain surface polarization, they pick up proteins called PINK1. These are degraded by healthy mitochondria but not by defective ones. PINK1 then brings in another protein called parkin The presence of sufficient parkin is the signal for a lysosome to engulf a mitochondrion and digest it, but of course it has to be small enough to fit into the lysosome to begin with.
 

When a mitochondrion becomes uncoupled, protein import to the inner mitochondrial membrane is prevented so PINK1 is diverted from PARL and accumulates on the outer mitochondrial membrane. This yields a sensor of mitochondrial damage that can flag an individual impaired mitochondrion in a milieu of healthy ones. PINK1 on a damaged mitochondrion, through its kinase activity, recruits the E3 ligase Parkin from the cytosol specifically to that impaired mitochondrion (Fig. 3). Once there, Parkin ubiquitinates outer mitochondrial membrane proteins and induces autophagic elimination of the flagged mitochondrion (21). 
 

 

 

Giant zombie mitochondria can build up when the normal fission/fusion process of the cell is not sufficient to divide them up. Thus one purpose of the protocol is to push fission to a greater degree than normally occurs. 

 

 

Very interesting. If this is how it works, then I suppose that the clonal expansion of defective mitochondria that is observed in my disease and lead to its progression must be a problem with fission. Maybe the residual ATP output does not allow the fission process to start.

 

Anyway, this opens a whole new way to think about my disease treatment. Thanks.



#807 Turnbuckle

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Posted 15 February 2018 - 07:27 PM

 

 

 

 

Very interesting. If this is how it works, then I suppose that the clonal expansion of defective mitochondria that is observed in my disease and lead to its progression must be a problem with fission. Maybe the residual ATP output does not allow the fission process to start.

 

Anyway, this opens a whole new way to think about my disease treatment. Thanks.

 

 

 

It might also result from a problem with the labeling of defective mitochondria (this has been shown in vitro in human cell lines, though not necessarily in vivo in mice)--

 

The involvement of Pink1 and Parkin in mitophagy suggests the intriguing hypothesis that some forms of PD may result from a loss of mitochondrial quality control, leading to the accumulation of dysfunctional mitochondria. PD has long been linked to mitochondrial dysfunction (Abou-Sleiman et al., 2006). Cell culture experiments suggest that Parkin can influence the segregation of mtDNA mutations in a heteroplasmic cell, biasing the population towards functional mtDNA (Suen et al., 2010). However, our knowledge of the Pink1/Parkin system in mitophagy is still preliminary. In some neuronal cultures, Parkin recruitment to depolarized mitochondria is not robust (Van Laar et al., 2011) or occurs with slower kinetics compared to commonly used cell lines, such as HeLa cells (Cai et al., 2012). In an experimental mouse model of mitochondrial dysfunction leading to neurodegeneration, Parkin is not recruited to damaged mitochondria and does not appear to play a significant protective role (Sterky et al., 2011). The latter result may also reflect differences between the role of Parkin in mice versus humans, because mice lacking Parkin or Pink1 do not show neurodegenerative changes. Therefore, it will be important to clarify the physiological functions of Parkin and mitophagy in mitochondrial disease.

https://www.ncbi.nlm...les/PMC4271190/

 

Sodium Benzoate is known to upregulate PINK1 and parkin. See Fig. 1F in Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons.


Edited by Turnbuckle, 15 February 2018 - 07:49 PM.

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#808 Nate-2004

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Posted 16 February 2018 - 02:36 PM

The metabolism of mice is so dramatically different than humans that I can't see how they're all that useful for studying the mechanisms of aging.

 

I've been adding cinnamon to my coffee for a couple of months now. Does this mean upregulating pink and parkin may assist in improving quality control during fission based on the process you described earlier?



#809 Turnbuckle

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Posted 16 February 2018 - 03:28 PM

 

 

I've been adding cinnamon to my coffee for a couple of months now. Does this mean upregulating pink and parkin may assist in improving quality control during fission based on the process you described earlier?

 

Yep, I expect it might help with some people when used in conjunction with fission.


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#810 stephen_b

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Posted 19 February 2018 - 04:14 AM

I have been giving the high energy protocol of post #746 a go for the past couple of days. I notice right away a lower heart rate, both resting heart rate (near 54 bpm, down almost 10 bpm) and exercising heart rate during a 6 mile run.

 

While my heart rate was lower than normal for the same effort and I felt more energy, I still felt off. Maybe it was a higher blood pressure (I wasn't able to measure it). Perhaps the dose is too high? I might try cutting it in half and going out for a run again tomorrow.







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