T3 intracellular calcium and caffeine

S-VV

Senior Member
Messages
225
Likes
247
And:

The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter (MCU)

Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU-/- mice have no apparent capacity to rapidly uptake calcium. While basal metabolism appears unaffected, the skeletal muscle of MCU-/- mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU-/- mice exhibited marked impairment in their ability to perform strenuous work
 

S-VV

Senior Member
Messages
225
Likes
247
I think this can be related to Navieaux theory of CDR and cells in the early stages limiting the calcium uptake or expression of MCU to switch from oxphos to glycolisis. Maybe forcing a higher concentration of calcium inside the mitochondria got you out of the CDR.

On the other hand, if someone has mutations in their calcium channels, the intracelular/ intra-mitochondrial Calcium couldn't be restored, and the signaling Cascade to exit CDR could not begin properly. Now where have we seen such mutations...

Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients

TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
So I took 200 mg of caffeine + 5 mg hydrocortizone and 500 mg of calcium. I'm also on 125 mcg t4 (tapering down once i stabalize).

This combo definitely forced my brain to turn on.
Yes that seems to be a possibility. If I'm reading the diagram correctly, Li inhinits IP breakdown into myo-inositol. Does that mean that IP can be converted to IP3 quicker and in a larger proportion?
Yes, I think that's what it means. That when you're on lithium more IP3 is available and cytoplasmic Ca gradient goes up - and therefore more calcium is able to enter the mitochondria. And since IP3 is phosphate, it might be part of the reason why calcium phosphate is so effective for me. One might also try adding inositol to the mix.
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
@Gingergrrl
Ionized calcium is a very common test. It's ordered in ER and on hospitalized patients all the time. Your doctor can order it or you can buy it on directlabs. It measures the fraction of calcium in the active form (similar to how free T3 measures the fraction of active thyroid hormone).

It needs to be done fasting and you would need to be off calcium and vitamin d supplements for a week. Yes, the T3 in Armour might be keeping your calcium up - so you might want to do it off T3 when you're feeling pretty hypothyroid to get the most accurate read.

I've never heard about these N-type calcium channel antibodies. Do you know if it act similar to a calcium channell blocker or does it act as an agonist on those channels (similar to Grave's antibodies that stimulate the receptor)?
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
I think this can be related to Navieaux theory of CDR and cells in the early stages limiting the calcium uptake or expression of MCU to switch from oxphos to glycolisis. Maybe forcing a higher concentration of calcium inside the mitochondria got you out of the CDR.

On the other hand, if someone has mutations in their calcium channels, the intracelular/ intra-mitochondrial Calcium couldn't be restored, and the signaling Cascade to exit CDR could not begin properly. Now where have we seen such mutations...

Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients

TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients
Very interesting!
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
Here's the full mechanism of action. Turns out it's a currently well established theory in psychopharmacology that lithium increases mitochondrial calcium.





Fig. 1. Role of mitochondria in intracellular calcium signaling.

Intracellular calcium level is maintained low, but two organelles, endoplasmic reticulum and mitochondria, have high levels of calcium. Mendelian diseases that accompany bipolar disorder are the diseases of these two organelles.

GPCR, G protein coupled receptor; PIP2, Phosphatidylinositol 4,5-bisphosphate; I-1-P, inositol 1-phosphate; IP3. Inositol triphosphate; IP3-R, inositol triphosphate receptor; Bcl-2, B-cell lymphoma 2.
 

S-VV

Senior Member
Messages
225
Likes
247
That's very interesting. Your high HTMA Ca, (suggesting low celular Ca), the low ionic Ca and the positive response to lithium are very indicative of low mitochondrial Calcium.

Now if we could find out why you initially felt better on T3 and then worse, it would be a great step forward. Did T3 move Ca into the cytosol/ mitochondria at the expense of Ca reserves elsewhere?
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
I think that's because taking external T3 is not physiologic (unless it's tiny doses under 1 mcg in slow release form which is a weak approximation of what would be released by thyroid gland itself).
Each peak dose of T3 creates a hyperthyroid spike which further depletes calcium reserves and forces the cells to shut down metabolic rate even further, to decrease cellular thyroid transport, deiodinaton, so by the time the dose wears off, you are actually left more hypothyroid and with less calcium in your cells than you had before - thus creating a vicious cycle of needing to increase the dose to achieve the same effect.

@debored13
 

debored13

Senior Member
Messages
1,828
Likes
1,984
Location
Vermont, school in Western MA
I think that's because taking external T3 is not physiologic (unless it's tiny doses under 1 mcg in slow release form which is a weak approximation of what would be released by thyroid gland itself).
Each peak dose of T3 creates a hyperthyroid spike which further depletes calcium reserves and forces the cells to shut down metabolic rate even further, to decrease cellular thyroid transport, deiodinaton, so by the time the dose wears off, you are actually left more hypothyroid and with less calcium in your cells than you had before - thus creating a vicious cycle of needing to increase the dose to achieve the same effect.

@debored13
You know i'm into the ray peat thing, but it's interesting as he is not into super high doses and says that the doses he recommends are physiological! but he's talking more in the 3-5 mcg range

I will eventually look more into this

One thing peat says tho is that T3 with a meal should be slow release essentially
 

S-VV

Senior Member
Messages
225
Likes
247
Then the correct approach would be to increase miyo
NCLX: The Mitochondrial Sodium Calcium Exchanger
Liron Boyman,1,* George S. B. Williams,1,2,* Daniel Khananshvili,3 Israel Sekler,4 and W. J. Lederer1
Author information ► Copyright and License information ► Disclaimer

Among its many functional similarities to other Na+/Ca2+ exchanger proteins is a unique feature: it efficiently mediates Li+/Ca2+ exchange (as well as Na+/Ca2+ exchange) and was therefore named NCLX.
One thing I don't get. The NCLX is an efflux exchanger of Ca out of the Mitochondria. Lithium can be efficiently exchanged for Ca. This raises cytosolic Ca, but wouldn't it lower mitochondrial Ca?
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
Then the correct approach would be to increase miyo


One thing I don't get. The NCLX is an efflux exchanger of Ca out of the Mitochondria. Lithium can be efficiently exchanged for Ca. This raises cytosolic Ca, but wouldn't it lower mitochondrial Ca?
I suspect that the concentration of lithium is negligible compared to the concentration of sodium, so the effect you get from the increased cytosolic gradient will override the minor losses from this one. That's just me speculating.
 

S-VV

Senior Member
Messages
225
Likes
247
I suspect that the concentration of lithium is negligible compared to the concentration of sodium, so the effect you get from the increased cytosolic gradient will override the minor losses from this one. That's just me speculating.
Makes sense, thanks! So, if we know that increasing [Ca]m can have therapeutic effects, what other substances may be employed?

We have two ways of increasing [Ca]m:

- Increase calcium in the cytosol, and let the gradient do the rest
- Increase the activity of the MCU
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
You know i'm into the ray peat thing, but it's interesting as he is not into super high doses and says that the doses he recommends are physiological! but he's talking more in the 3-5 mcg range

I will eventually look more into this

One thing peat says tho is that T3 with a meal should be slow release essentially
Ray Peat is an interesting guy but to my knowledge he did not have ME/CFS or POTS so his experience would not be relevant to my own. This is why I have nothing to debate with him - he and I do not have the same condition. I suspect that he was probably treating himself for depression with high doses of thyroid. People with depression generally tend to respond well to high doses of T3 while people while people with severe CFS do not. There is a blog from a guy in Australia who went from having moderate CFS to not being able to leave his bed for the last ten years after taking T3 for a couple weeks.

It's also my impression that Ray Peat no longer believes most of what he said a long time ago, which is why he removed all his books and has tried to distance himself from the disciples who developed protocols based on his ideas since he's against any "protocols" and mainly tried to teach people to make intuitive connections about their bodies, his "perceive. think. act" mantra.
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
Makes sense, thanks! So, if we know that increasing [Ca]m can have therapeutic effects, what other substances may be employed?

We have two ways of increasing [Ca]m:

- Increase calcium in the cytosol, and let the gradient do the rest
- Increase the activity of the MCU
It looks like MCU is so new that all the treatments are still in the early experimental stage so cytosolic calcium is probably the best bet for us at this time.
 

Gingergrrl

Senior Member
Messages
13,564
Likes
39,987
@Gingergrrl Ionized calcium is a very common test. It's ordered in ER and on hospitalized patients all the time. Your doctor can order it or you can buy it on directlabs. It measures the fraction of calcium in the active form (similar to how free T3 measures the fraction of active thyroid hormone).
Would this test normally not be done outside of the ER or hospital (or would that be unusual)? My main doctor would order it if I asked him but I'd need to explain why I want it and how it would help or change my treatment. Once someone knows their level of ionized calcium (or active form?), what does that tell you from a treatment perspective?

It needs to be done fasting and you would need to be off calcium and vitamin d supplements for a week. Yes, the T3 in Armour might be keeping your calcium up - so you might want to do it off T3 when you're feeling pretty hypothyroid to get the most accurate read.
Fasting is no problem for me but I would not be able to stop Armour Thyroid or Vitamin D for a week so I guess I wouldn't be able to do this test anyway.

I've never heard about these N-type calcium channel antibodies. Do you know if it act similar to a calcium channell blocker or does it act as an agonist on those channels (similar to Grave's antibodies that stimulate the receptor)?
They are considered "paraneoplastic autoantibodies" and the Mayo Panels can test both the N-type and the P/Q type which often correlate with LEMS or Small Cell Lung Cancer (SCLC) but other times they are random and do not correlate with any known illness.

The Neuros that I saw told me explicitly that they act as a calcium channel blockers and I accepted this at face value and assume it to be accurate (although I cannot tell you why or how they work). I am negative for the P/Q type and positive for the N-type. There is also an L-type but I do not believe there is a test for this one.

I have Hashimoto's (both Hashi's autoantibodies and hypothyroid when not on Armour) but I don't know much re: Graves. I was tested for the Graves autoantibody once, just to rule it out, and it was negative.

It looks like MCU is so new
I read the prior posts but did not understand what MCU was. Is it an experimental med that acts as a calcium channel opener (like what Drob31 mentioned above) or something different?
 

pattismith

Senior Member
Messages
1,800
Likes
2,870
I agree and can't believe that I some how missed this entire thread until tonight! I hope it is okay that I am late to join the calcium party...

I would love input from everyone in this thread since I have the N-type Calcium Channel Autoantibody and have been told NOT to take any meds that further block the calcium channel. I also have Hashimoto's Disease and take Armour Thyroid which contains T3 (and do very well with it). And now that my POTS is basically in remission, I can drink coffee and lattes again and do well with them (although I still usually drink decaf to be safe).



Patti, do you mean that T3 and caffeine actually unblock the calcium channels (or am I misunderstanding this)?
T3 and caffeine only open calcium channels from the sarcoplasmic reticulum (a place inside the cell where calcium is stored), but I don't know which chanels are activated (maybe the RyR?)
However, these channels are differents from the calcium voltage gated channels , and I don't know if caffeine have any effect on these ones.

 

Gingergrrl

Senior Member
Messages
13,564
Likes
39,987
T3 and caffeine only open calcium channels from the sarcoplasmic reticulum (a place inside the cell where calcium is stored), but I don't know which chanels are activated (maybe the RyR?) However, these channels are differents from the calcium voltage gated channels , and I don't know if caffeine have any effect on these ones.
Patti, Thanks for explaining that (re: T3 and caffeine opening only certain CA+ Channels that are not the voltage gated ones). I assume most of this thread doesn't pertain to my situation after all but I was not certain (and it was interesting to read regardless)!
 

Iritu1021

Breaking Through The Fog
Messages
569
Likes
720
Fasting is no problem for me but I would not be able to stop Armour Thyroid or Vitamin D for a week so I guess I wouldn't be able to do this test anyway.
You can try doing it without stopping, just don't take Armour until after the test. It might not be accurate but still worth a try.

I have Hashimoto's (both Hashi's autoantibodies and hypothyroid when not on Armour) but I don't know much re: Graves. I was tested for the Graves autoantibody once, just to rule it out, and it was negative.
I only used Grave's as an example of an activating antibody. I have Hashimoto's too.

I read the prior posts but did not understand what MCU was. Is it an experimental med that acts as a calcium channel opener (like what Drob31 mentioned above) or something different?
It's a recently discovered protein transporter that uptakes calcium into mitochondria. The channels you are talking about are in the cellular membranes but I suppose that if you have something that blocks Ca entrance into cells it will lead to low intracellular calcium and therefore low mitochondrial calcium, which in turn leads to mitochondrial dysfunction.