2287 replies to this topic

[Turnbuckle]

 

Turnbuckle took me here from here

 

In my case, where a given percentage of my mitochondria are faulty, fusion is the recommended approach:

 

 

 

 Our results provide strong experimental support for this hypothesis and suggest that mitochondrial fusion may ameliorate the clinical severity of inherited mtDNA encephalomyopathies

 

 

Fusion may ameliorate the severity in the short term, but it does absolutely nothing to get rid of defective mtDNA. If you have a sub population of normal mtDNA, however, fission/fusion might help.

[mitomutant]

Yes, my condition is heteroplasmic. In the muscle biopsy, it seemed like 30%-35% of my mitochondria were mutant (and faulty, unable to produce any ATP at all).

[Turnbuckle]

Yes, my condition is heteroplasmic. In the muscle biopsy, it seemed like 30%-35% of my mitochondria were mutant (and faulty, unable to produce any ATP at all).

 

 

Old people have either the same or an analogous situation--defective mitochondria build up and the normal QC process fails to get rid of them. This severity of the problem is hidden by the fact that mitochondria typically have a number of mtDNA loops, and just one can produce enough proteins to keep it running--

 

For example, 20% of normal mtDNAs within a cell can mask the respiratory-deficient phenotypic of 80% 3243A>G mutant mtDNAs 

https://www.ncbi.nlm...les/PMC3809581/

 

 

Thus I wonder about 30-35% of your mitochondria not being able to produce any ATP at all. If that is true, then you likely have a far larger amount of defective mtDNA than 30-35%, along with defective mito QC that allowed this situation to develop.

 

Could this protocol help you? Possibly, if the deficiency is merely a lack of fission. If it is in the labeling of defective mitochondria for mitophagy, possibly the stimulating of the genes involved could help. The process of labeling defective mitochondria has a lot of parts, and thus it could go wrong in many different ways--

 

 

The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

 

Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1–PARKIN pathway will be critical for our understanding of mitochondrial quality control.

 

http://genesdev.cshl...ntent/29/10/989

 

 

 

See also this post re up-regulating PINK1 and PARKIN. 

Edited by Turnbuckle, 15 November 2017 - 10:47 AM.

[mitomutant]

 

For example, 20% of normal mtDNAs within a cell can mask the respiratory-deficient phenotypic of 80% 3243A>G mutant mtDNAs 

 

Thus I wonder about 30-35% of your mitochondria not being able to produce any ATP at all. If that is true, then you likely have a far larger amount of defective mtDNA than 30-35%, along with defective mito QC that allowed this situation to develop.For example, 20% of normal mtDNAs within a cell can mask the respiratory-deficient phenotypic of 80% 3243A>G mutant mtDNAs 

 

 

 

This is known as the threshold effect and it has to be very high before developing clinical phenotypes of a given genetic mutation. I have almost total paralysis of my extraocular muscles, so the mutation rate here must be >80-90%. However, I can workout normally and I have normal strength (p.e. I can easily squat my bodyweight), so that the mutation ratio in my limbs is much lower.

 

As you probably know, mutant mitochondria has a replication advantage over wild type mitochondria. This is known as "clonal expansion" of defective mitos and it is what causes disease progression. I started to develop ptosis in my 20' and diplopia in my 30', so you can clearly see that I was born with a much lower mutation ratio.

 

 

 

If it is in the labeling of defective mitochondria for mitophagy

 

Very likely. It is speculated that mutant mitochondria go under the radar and are not tagged for mitophagy because the residual ATP and ROS they produce is not enough to initiate the cascade of events that ultimately lead to mitophagy.

[Turnbuckle]

 

 

 

 

 

If it is in the labeling of defective mitochondria for mitophagy

 

Very likely. It is speculated that mutant mitochondria go under the radar and are not tagged for mitophagy because the residual ATP and ROS they produce is not enough to initiate the cascade of events that ultimately lead to mitophagy.

 

 

So how about fission + a weak uncoupler?

[mitomutant]

 

 

So how about fission + a weak uncoupler?

 

Could not agree more! I was speculating with DNP for a while, but I decided not to because of its narrow therapeutic index. I also considered plain old aspirin but then, I have not tried it in a consistent manner.

 

What uncoupler would you recommend ?

 

Thanks

 

[Turnbuckle]

 

 

 

So how about fission + a weak uncoupler?

 

Could not agree more! I was speculating with DNP for a while, but I decided not to because of its narrow therapeutic index. I also considered plain old aspirin but then, I have not tried it in a consistent manner.

 

What uncoupler would you recommend ?

 

Thanks

 

 

I have minimal experience with uncouplers, but it would seem wise to try fission alone first, then fission with uncouplers of increasing strength. FFAs are weak uncouplers, and vegetable oils without stearic acid would be best, as stearic acid promotes fusion--

 

Interaction of free fatty acids with mitochondria: Coupling, uncoupling and permeability transition

 

At micromolar concentrations FFA increase the proton conductance of the inner membrane acting as protonophores. FFA can act as natural uncouplers, causing a mild uncoupling, which prevents reactive oxygen species production in the respiratory resting state.

 

http://www.sciencedi...005272806000958

 

 

Avocado oil has only a trace of stearic acid, typically 0.1%. I've tried it--a couple of tablespoons--and it does seem to increase the weakening effect I see with fission. (Of course vegetable oils are not FFAs, but they will be freed during metabolism.)

Edited by Turnbuckle, 15 November 2017 - 01:50 PM.

[Nate-2004]

While Aspirin has its problems with gut damage over time it's probably safe to use once a day just during the fission cycle isn't it?

 

Someone linked to a post on the old thread about zombie mitochondria and Turnbuckle mentioned Cinnamon as a means of upregulating PINK and PARKIN, is this just plain old cinnamon that you buy in the spice isle or a special extract of it?

 

EDIT: I'm betting the MCT oil I take has been acting as an uncoupler?

Edited by Nate-2004, 15 November 2017 - 01:51 PM.

[Turnbuckle]

While Aspirin has its problems with gut damage over time it's probably safe to use once a day just during the fission cycle isn't it?

 

Someone linked to a post on the old thread about zombie mitochondria and Turnbuckle mentioned Cinnamon as a means of upregulating PINK and PARKIN, is this just plain old cinnamon that you buy in the spice isle or a special extract of it?

 

EDIT: I'm betting the MCT oil I take has been acting as an uncoupler?

 

 

MCT oil? Seems unlikely, as the FAs are too short. The paper I linked to above focused on arachidonic acid. This can both uncouple or uncouple depending on the dosage, so maybe that is not the best either.

Edited by Turnbuckle, 15 November 2017 - 02:46 PM.

[Nate-2004]

Berberine, while it is an AMPK activator, also down regulates the uncoupling protein.

 

 

[ambivalent]

 

The kidney pain that was so severe, I nearly called for an ambulance, followed the day after stopping NR because of the new benchmark of extremity pain. The extremity pain is undoubtedly NR or N+R - I'd experienced this when just on NR as have others.

 

There is also a dizziness I've experienced when first taking NR which I knew to be the same dizziness frequently experienced 15-20 years prior when my blood-glucose was undoubtedly very high from an extremely sugar diet. I have no doubt that NR and possibly N+R are responsible for the extremity pain (incidentally my feet still felt 'bruised' even now ): it is way too strongly correlated. The uncertainty resided as to whether it was responsible for triggering kidney damage of which I've never experienced the like of.

 

The possibility that these two events are unrelated seems rather unlikely - it is a question of whether it was direct or indirect (such as stirring up kidney stones, say).

 

 

 

If connected, could be the ribose. It appears that ribose can raise uric acid in some people, and that can produce UA stones.

 

 

 

Update: Following this suggestion, I decided to see if cherry juice, known for reducing uric acid, would work. And it did. No flank pain for two weeks; very occasional lower back 'kidney' pain. The needling sensations all around my body took a few days to go. My feet, however, are a different issue - I still have regular pains, especially in the morning on the soles. If I take cherry juice and or celery seeds the pain goes away, but it is temporary. It appears diet related; I rather shamefully had a couple of spare slices of some cake yesterday - instant increase in foot pain (indulgences are occasional) and the pain was worse today but very good the previous day following a healthy diet. Sugar can increase uric acid, but also I'm concerned there may well be a blood glucose problem too.

 

I may well be predisposed to uric acid problems (father) but I have also consumed considerable amounts of tea and coffee in recent months. In addition I've started taking aspirin intermittently over the last couple of months, which I see from another thread a user has claimed it contributes to gout. and another to kidney pain

 

In addition to d-ribose and uric acid there is an implication on webmd that 'niacin' affects uric acid levels (unfortunately, I can't link from this device). It says

 

Monitor for blood sugar levels if you have diabetes and uric acid levels if you have gout.

 

I have no more substantive references at the moment.

 

Incidentally, despite these troubles I've had no gout recently, but did last year on one finger whilst taking NR. I believe it has also been expressed in the NR experiences thread.

 

Obviously a great deal of improvement, so thanks TB, but still problems of either I suspect BG and or Uric Acid. One cautionary note I read stated high uric acid levels to be asymptomatic up until the point where real problems kick in. Two days before the stones dropped me, I felt fabulous, despite some extremity pain. I may well have been an outlier, but it is probably worth keeping an eye on UA levels if undertaking this protocol. Speaking of which I certainly need some blood work.

 

   

 

 

[mitomutant]

Avocado oil has only a trace of stearic acid, typically 0.1%. I've tried it--a couple of tablespoons--and it does seem to increase the weakening effect I see with fission. (Of course vegetable oils are not FFAs, but they will be freed during metabolism.)

 
Ahh, I was thinking of synthetic uncouplers. I have just re-read an old paper I had about a new class of uncouplers with a wide therapeutic index that would fit nicely here:
 
 

 
 

Mitochondrial uncoupling is an effective way to reduce body weight in humans, but using uncouplers such as DNP is problematic because the toxic dose is close to the therapeutic dose. The problem is the steep concentration-dependence of uncoupling by DNP and other conventional uncouplers. Unlike DNP, BHT partially uncoupled mitochondria and cells at extremely low concentrations. This uncoupling was only slightly dependent on concentration, leading to the extraordinarily wide dynamic range of uncoupling by BHT.[/size] [/size] 

Anyway, the FFA path seems interesting as well. Thanks.

[brosci]

I wish there was an easier way to add up the fatty acid chains in my diet -- I often eat keto and would be very interested to see how total stearic acid adds up, or other metrics (like total palmitic or palmitoleic.)

 

Eating 2oz of dark chocolate looks like it provides 5g of stearic acid in one snack.  I believe the polyphenols are also associated with mitochondrial biogenesis.  I've seen Capric acid mentioned to have unique benefits -- for a while, I was doing semi-frozen MCT-Oil chocolates dubbed "fat bombs."

 

https://www.ncbi.nlm...pubmed/24383952

Edited by brosci, 20 November 2017 - 07:53 AM.

[Nate-2004]

Should AMPK activators not be taken during fission, or only during fusion? Somehow I keep getting things mixed up. What about resveratrol and lithium?

[PAMPAGUY]

Alive by Nature has a new site on Facebook,(NMN Plus)and invited me to join because I was a previous user. In return they are sending me a bottle of there new product NMN+. Can hardly wait. 125 mg NMN + other precusors. After learning about N+R it makes you mad about the prices these guys are charging for NR and NMN.

On another note, stopped taking Metformin on Fision days. Feel much better. It's an uncoupler as Turnbull said. Got some Ribose and took a gram with my NR. Had less fatique.

Protocol is:

2 days of fission with N(1.5gm) + R(3gm), 1 day off, 3 days fusion with stearic acid 10 gm on 1st 2 days, last day PQQ 20gm, brocolli max 2 caps. 1 day off before next
cycle. Bought 2 lbs each of N and R in powder.

See how I feel and go from there.

[stephen_b]

This protocol calls for inducing mitochcondrial biogenesis on fusion days. Is NR itself, taken on fission days, the heavyweight though when it comes to biogenesis? PMID 22682224:

 

 

 

Altogether, these results suggest that NR feeding increases mitochondrial biogenesis in a tissue-specific manner, consistent with the tissue-specific nature of the increases in NAD+ and sirtuin activity observed in NR-fed mice. The higher number of mitochondria, together with the different morphological mitochondrial profiles found in NR-fed mice (Fig.4C) would contribute to explain the higher oxidative profile, energy expenditure and protection against metabolic damage observed upon NR feeding.

 

[Turnbuckle]

 

This protocol calls for inducing mitochcondrial biogenesis on fusion days. Is NR itself, taken on fission days, the heavyweight though when it comes to biogenesis? PMID 22682224:

 

 

 

Altogether, these results suggest that NR feeding increases mitochondrial biogenesis in a tissue-specific manner, consistent with the tissue-specific nature of the increases in NAD+ and sirtuin activity observed in NR-fed mice. The higher number of mitochondria, together with the different morphological mitochondrial profiles found in NR-fed mice (Fig.4C) would contribute to explain the higher oxidative profile, energy expenditure and protection against metabolic damage observed upon NR feeding.

 

 

 

It's a little hard to say how this would translate to humans, or to this protocol. For one thing, the mice were only ten weeks old, and thus would have few defective mitochondria to eliminate. In another study, the dosing of human cells with NAM showed considerable decrease in mtDNA through mitophagy. See this post.

 

In your linked mice study with NR, the mitochondria were actually 50% lager than the control, which suggests that fission was no longer occurring with chronic feeding. In fact, it appears that the mice mitochondria were in a state of relative fusion. See Fig. 4. Ultimately this would be a problem as mitophagy requires fission.

[PAMPAGUY]

Turnbuckle,
You had mentioned that Sulforaphane lowered your B/P when you took it. According to this French supplement company Sulforaphane has no known effects on B/P. This Co. is suppose to have best Sulforaphane, but most expensive. You might want to check your other supplements for the cause. http://www.prostapha...-questions.html

On another note, Broccmax seems to be the best brand with 8 mg active Sulforaphane. The above Sulforaphane has 10 mg.

[Adam1]

Stephen, I think our network of pathways can respond to opposite signals without neutralizing them, so merging the two phases of this protocol is not necessarily out of the question. NR is not the only compound implicated for opposite actions such as mitophagy and mitogenesis. Physiologically, these opposites tend to generate each other, and sometimes a single substance can potentiate two opposite effects (see other thread).

 

Turnbuckle, I appreciate the bold thinking behind this protocol. However, I would consider some tweaking in light of the paradigm discussed in “On the Network Properties of Mitochondria”:*

 

The major insight from these studies is that mitochondria act as a network of coupled oscillators with the potential for active intracellular ROS signaling through a frequency- and amplitude-encoded process.

 

I don’t think the span for the cycles in the protocol can accommodate real-time “rapid fission, fusion, and translocation events.” My concern is that a linear bipolar model potentially constrains fluidity of the non-linear dynamics.

While the human mind is incapable of conceiving a thing and its opposite at the same time, the human body’s signalling pathways are actually performing simultaneous opposites, with cycles emerging out of an interplay of chaos. It’s helpful to provide hormetic nudges that disrupt homeostasis only to strengthen it. It’s not necessarily helpful to try to put the network on a set of rails. So I am thinking a recovery period of no intervention might be useful after each phase, to give the chaos of mitochondrial respiration some breathing room.

 

*Aon, M. A., Cortassa, S. and O'Rourke, B. (2007) On the Network Properties of Mitochondria, in Molecular System Bioenergetics: Energy for Life (ed V. Saks), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi: 10.1002/9783527621095.ch4

[Turnbuckle]

Turnbuckle,
You had mentioned that Sulforaphane lowered your B/P when you took it.

 

This was when used with the protocol, not when used alone. However, in spontaneously hypertensive rats it has been found to lower blood pressure. See this post. 

[Turnbuckle]

Stephen, I think our network of pathways can respond to opposite signals without neutralizing them, so merging the two phases of this protocol is not necessarily out of the question. NR is not the only compound implicated for opposite actions such as mitophagy and mitogenesis. Physiologically, these opposites tend to generate each other, and sometimes a single substance can potentiate two opposite effects (see other thread).

 

Turnbuckle, I appreciate the bold thinking behind this protocol. However, I would consider some tweaking in light of the paradigm discussed in “On the Network Properties of Mitochondria”:*

 

The major insight from these studies is that mitochondria act as a network of coupled oscillators with the potential for active intracellular ROS signaling through a frequency- and amplitude-encoded process.

 

I don’t think the span for the cycles in the protocol can accommodate real-time “rapid fission, fusion, and translocation events.” My concern is that a linear bipolar model potentially constrains fluidity of the non-linear dynamics.

While the human mind is incapable of conceiving a thing and its opposite at the same time, the human body’s signalling pathways are actually performing simultaneous opposites, with cycles emerging out of an interplay of chaos. It’s helpful to provide hormetic nudges that disrupt homeostasis only to strengthen it. It’s not necessarily helpful to try to put the network on a set of rails. So I am thinking a recovery period of no intervention might be useful after each phase, to give the chaos of mitochondrial respiration some breathing room.

 

*Aon, M. A., Cortassa, S. and O'Rourke, B. (2007) On the Network Properties of Mitochondria, in Molecular System Bioenergetics: Energy for Life (ed V. Saks), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi: 10.1002/9783527621095.ch4

 

Loopy speculation with a lot of buzz words, in my opinion. They need to put some data to it. As for adding a recovery period with no intervention, I don't see any problem with that. And as for the "fluidity of the non-linear dynamics," expect that fluidity is not lost, but the center-point is pushed first in one direction, then the other--a slow oscillation that operates in the background to the rapid activity of mitochondria. 

[Adam1]

Actually as mentioned in the quote above, there is evidence (“The major insight from these studies is…”). I think part of the shift in medical thinking is driven by advances in computational modelling. The math is a bit beyond me, but I would not call it loopy. When we are inducing local perturbations we need to have enough evidence supporting what we are doing, to know that we are maintaining global stability. You don’t want local failures to scale up to higher levels of organization.

[Turnbuckle]

Actually as mentioned in the quote above, there is evidence

 

Can you link to this evidence?

[Adam1]

Sure, 129 references in the small chapter (Aon, M. A., Cortassa, S. and O'Rourke, B. (2007) On the Network Properties of Mitochondria, in Molecular System Bioenergetics: Energy for Life (ed V. Saks), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi: 10.1002/9783527621095.ch4.)

 

Turnbuckle, when you said you “expect that fluidity is not lost,” did you have evidence for that? When you spoke of “a slow oscillation that operates in the background to the rapid activity of mitochondria” what were you saying was oscillating slowly?

 

It’s important because mitochondria govern life and death*, and we need sufficient evidence that any protocol for mitochondria allows the network the resilience it requires.

 

*O’Rourke, Brian, Sonia Cortassa, and Miguel A. Aon. "Mitochondrial ion channels: gatekeepers of life and death." Physiology 20.5 (2005): 303-315.

*Aon, Miguel Antonio, et al. "Mitochondrial criticality: A new concept at the turning point of life or death." Biochim Biophys Acta 1762.2 (2006): 232-240.

[PAMPAGUY]

Well the Elysium 8 wk trial is published and it was kind of a bust. The 500 mg NR dose jumped up NAD 90% in 4 weeks, and just continued to decline after that to 45-50%. So our N+R protocal of 1.5g N + 3g R would seem to be approprate.

https://www.nature.c...1514-017-0016-9

Edited by PAMPAGUY, 28 November 2017 - 07:35 PM.

[Nate-2004]

Well the Elysium 8 wk trial is published and it was kind of a bust. The 500 mg NR dose jumped up NAD 90% in 4 weeks, and just continued to decline after that to 45-50%. So our N+R protocal of 1.5g N + 3g R would seem to be approprate.

https://www.nature.c...1514-017-0016-9

 

NAMPT falls when NAD+ is high correct? So you get less need for recycling. I don't see why this necessarily makes N+R appropriate. However, any positive results from a study funded by a company that profits from positive results should definitely be taken with a grain of salt.

 

Also, with the protocol relevant to this thread's discussion, we're only taking NR (those of us doing NR instead of N+R) for 3 or 4 days out of 7. Not chronically for 8 weeks straight.

 

Side note: I'm really hesitant to do any more than a 1:1 ratio of N+R anyway, in fact I'm doing more like N:R 1:0.8, worried that too much R can be bad.

Edited by Nate-2004, 28 November 2017 - 08:48 PM.

[Adam1]

Just to clarify my concern: synchrony. The idea that the induced slow oscillations are always situated in the background cannot be assumed when there is evidence the network of mitochondria can oscillate synchronously. Turnbuckle, you seem to be suggesting the protocol is really for some slow modulation process behind rapid mitochondria free to shift as needed, but why is that necessarily so?

 

 

Local intermitochondrial coupling can be mediated by reactive oxygen species (ROS) that activate inner membrane pores to initiate a ROS-induced-ROS-release process that produces synchronized limit cycle oscillations of mitochondrial clusters within the whole mitochondrial network.

Kurz F.T., Aon M.A., O’Rourke B., Armoundas A.A. (2017) Functional Implications of Cardiac Mitochondria Clustering. In: Santulli G. (eds) Mitochondrial Dynamics in Cardiovascular Medicine. Advances in Experimental Medicine and Biology, vol 982. Springer, Cham

We explore in a detailed example the success of experimental–modeling synergy leading to the elucidation of the mechanisms involved in synchronized mitochondrial oscillations in the heart, and the discovery there of new related mechanisms. This work involves successive and iterative reciprocal potentiation of the loop via experiments and computational modeling: simulation–validation and prediction– experimentation thereby alternate so as to provide a deeper understanding of complex biological phenomena.
 

Cortassa S., Aon M.A. (2014) Dynamics of Mitochondrial Redox and Energy Networks: Insights from an Experimental–Computational Synergy. In: Aon M., Saks V., Schlattner U. (eds) Systems Biology of Metabolic and Signaling Networks. Springer Series in Biophysics, vol 16. Springer, Berlin, Heidelberg

 

Why does it matter? Because poorly induced mitochondrial dynamics can cause death:

 

 

 

The ROS-dependent mitochondrial oscillator described in cardiac cells exhibits at least two modes of function under physiological conditions or in response to metabolic and oxidative stress. Both modes depend upon network behavior of mitochondria. Under physiological conditions cardiac mitochondria behave as a network of coupled oscillators with a broad range of frequencies. ROS weakly couples mitochondria under normal conditions but becomes a strong coupling messenger when, under oxidative stress, the mitochondrial network attains criticality. Mitochondrial criticality is achieved when a threshold of ROS is overcome and a certain density of mitochondria forms a cluster that spans the whole cell. Under these conditions, the slightest perturbation triggers a cell wide collapse of the mitochondrial membrane potential, ΔΨ_m, visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in ΔΨ_m, NADH, ROS, and GSH. This dynamic behavior scales from the mitochondrion to the cell by driving cellular excitability and the whole heart into catastrophic arrhythmias. A network collapse of ΔΨ_m under criticality leads to: i) energetic failure, ii) temporal and regional alterations in action potential (AP), iii) development of zones of impaired conduction in the myocardium, and, ultimately, iv) a fatal ventricular arrhythmia.

 

Aon MA, Cortassa S, Akar FG, Brown DA, Zhou L, O’Rourke B. FROM MITOCHONDRIAL DYNAMICS TO ARRHYTHMIAS. The international journal of biochemistry & cell biology. 2009;41(10):1940-1948. doi:10.1016/j.biocel.2009.02.016.

 

[PAMPAGUY]

Don't know the ratio of N vs R in NR. Do you? Just received my N and R, but was taking NR before that. Always felt washed out on days of NR, so starting taking 1gm R with the NR. It seemed to help, but cleaning out those zombies is hard work. Took 1st 2 doses(Sun and Mon) of N .8 gm + R 2 gm at nite with Trytophane 1 gm. Slept really well while the heavy lifting goes on. Took Tues. off, but will start Fusion tomorrow with 10g of Stearic acid

[Turnbuckle]

Don't know the ratio of N vs R in NR. Do you? Just received my N and R, but was taking NR before that. Always felt washed out on days of NR, so starting taking 1gm R with the NR. It seemed to help, but cleaning out those zombies is hard work. Took 1st 2 doses(Sun and Mon) of N .8 gm + R 2 gm at nite with Trytophane 1 gm. Slept really well while the heavy lifting goes on. Took Tues. off, but will start Fusion tomorrow with 10g of Stearic acid

 

 

To achieve a stoichiometric dose for N+R, use 45% nicotinamide and 55% ribose. (Nicotinamide has a molecular weight of 122.13 and ribose 150.13.) But 50/50 should be fine.

[Turnbuckle]

 

Why does it matter? Because poorly induced mitochondrial dynamics can cause death:

 

 

 

The ROS-dependent mitochondrial oscillator described in cardiac cells exhibits at least two modes of function under physiological conditions or in response to metabolic and oxidative stress. Both modes depend upon network behavior of mitochondria. Under physiological conditions cardiac mitochondria behave as a network of coupled oscillators with a broad range of frequencies. ROS weakly couples mitochondria under normal conditions but becomes a strong coupling messenger when, under oxidative stress, the mitochondrial network attains criticality. Mitochondrial criticality is achieved when a threshold of ROS is overcome and a certain density of mitochondria forms a cluster that spans the whole cell. Under these conditions, the slightest perturbation triggers a cell wide collapse of the mitochondrial membrane potential, ΔΨ_m, visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in ΔΨ_m, NADH, ROS, and GSH. This dynamic behavior scales from the mitochondrion to the cell by driving cellular excitability and the whole heart into catastrophic arrhythmias. A network collapse of ΔΨ_m under criticality leads to: i) energetic failure, ii) temporal and regional alterations in action potential (AP), iii) development of zones of impaired conduction in the myocardium, and, ultimately, iv) a fatal ventricular arrhythmia.

 

Aon MA, Cortassa S, Akar FG, Brown DA, Zhou L, O’Rourke B. FROM MITOCHONDRIAL DYNAMICS TO ARRHYTHMIAS. The international journal of biochemistry & cell biology. 2009;41(10):1940-1948. doi:10.1016/j.biocel.2009.02.016.

 

 

I used several versions of the protocol for more than six months and didn't note any arrhythmia, but certainly anyone with arrhythmia ought to use this protocol with caution. And if anyone has noted any arrhythmia while using the protocol, please mention it on this thread.