Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

[wastwater]

I was looking at sensorineural deafness and saw a few articles mentioning hsp70 and an autoimmune sensorineural deafness think it mentions antibodies against hsp70

 

[PinkPanda]

https://forums.phoenixrising.me/index.php?attachments/blood-gas-results-jpg.21391/

I've been looking into hypoxia as a cause of a lot of complications in chronic disorders and was interested to note that even a small drop in PO2 can have extreme effect on some people but you might be interested to know that this revolves a lot around around HIF-1 (hypoxia inducible factor 1) and I see that HIF-1 is implicated as one of the novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation.

I've been looking into low oxygen saturation lately:

The following physiological factors influence the affinity of hemoglobin for oxygen:

• The partial pressure of CO2
• pH, independent of CO2
• The concentration of 2,3-DPG inside the erythrocytes
• The presence of unusual haemoglobin species
• Temperature

The effect of 2,3-DPG on haemoglobin is profound. It is probably the most important allosteric effector of positive cooperativity. In brief, the presence of 2,3-DPG stabilises the T state of deoxyhaemoglobin, decreasing its affinity for oxygen. This was explored in a seminal paper by The Benesches of Columbia University (1967). (All these T and R state changes are discussed elsewhere, and one will not digress here into discussing the inaccuracy of the R-T model and the existence of numerous structural haemoglobin variants.)

http://derangedphysiology.com/main/core-topics-intensive-care/arterial-blood-gas-interpretation/Chapter 4.0.5/factors-which-influence-affinity-haemoglobin-oxygen
2,3-DPG= 2,3-Biphosphoglycerate
The first diagram in this link is good too.

2,3-DPG is synthesized from 1,3-Biphosphoglycerate, a metabolite of the glycolysis pathway (picture).

Acidic pH/lactate can also reduce oxygen saturation, but on second thought that seems disproportionate, since your oxygen saturation is constantly too low and lactate only elevated in the second measurement.
I'm still looking into reasons for high 2,3-DPG.

Application of the calcium chelator BAPTA induced HIF-1α protein levels in normoxia and enhanced HIF-1α protein accumulation under hypoxic conditions. Maximum HIF-1α protein induction was observed after 1 h of incubation with BAPTA-AM (Fig. 1). In contrast, elevation of intracellular calcium using thapsigargin diminished hypoxia-induced HIF-1α protein levels after incubation from 0.5 to 4 h (Fig. 1).

http://www.jbc.org/content/279/43/44976.full

I don't know if diminishing HIF-1α protein would be a good thing, but it seems to interact with calcium signaling.

This is a bit speculative, but maybe your calcium excretion inside the cell is rather low, also since you have high calcium in the blood. :thumbdown: High calcium excretion from the ER can lower blood calcium by refilling the low ER store by pulling calcium from the blood through store-operated-channels/ calcium-release-activated-channels.

The major Ca2+ entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca2+ stores activates Ca2+ influx (store-operated Ca2+ entry, or capacitative Ca2+ entry). This is often referred to as the store-operated current or SOC.[5]
A common mechanism by which such cytoplasmic calcium signals are generated involves receptors that are coupled to the activation of phospholipase C. Phospholipase C generates inositol 1,4,5-trisphosphate (IP3), which in turn mediates the discharge of Ca2+ from intracellular stores (components of the endoplasmic reticulum), allowing calcium to be released into the cytosol. In most of the cell, the fall in Ca2+ concentration within the lumen of the Ca2+-storing organelles subsequently activates plasma membrane Ca2+ channels.

https://en.wikipedia.org/wiki/Calcium_release_activated_channel

Store-operated channels (SOCs) are ion channels located in the plasma membrane of all non-excitable cells (all cells except myocytes, neurons and endocrine cells). These channels are most studied in regard to their role in calcium entry into the cytoplasm from extracellular milieu.

https://en.wikipedia.org/wiki/SOC_channels

Edit: I'm sorry, I take that back on the low intracellular calcium. I've been looking into the issue more and I think it may be more complicated.

 

[PinkPanda]

In general on the oxygen saturation, as I understand it, the oxygen dissociation curve describes how easily oxygen binds to hemoglobin. When curve is shifted more to the right, hemoglobin binds less to oxygen/ dissociates more from oxygen. This leads to more oxygen being released to tissues, but also less oxygen being bound to transport to tissues.

For me, it would be logical that both extremes can cause problems. When oxygen is bound too strong, it isn't released to tissues, when oxygen affinity is too low, it isn't bound at all to transport to tissues. You have higher lactate in the second measurement, while oxygen saturation is better, that supports that lactate/low pH is not the sole/decisive factor that reduces your oxygen saturation.
And your CO2 is low, so high CO2 can't cause low oxygen saturation for you either.

I've been looking into causes of high 2,3-DPG. What doesn't fit is that high pH increases 2,3-DPG, while low/ acidic pH decreases 2,3-DPG. With your lactate you shouldn't have high 2,3-DPG.
Another factor are phosphate levels. High phosphate can increase 2,3-DPG.

An increase in 2,3-DPG concentration is found in most conditions in which the arterial blood is undersaturated with oxygen, as in congenital heart and chronic lung diseases, in most acquired anaemias, at high altitudes, in alkalosis and in hyperphosphataemia. Decreased 2,3-DPG levels occur in hypophosphataemic states and in acidosis.

https://www.sciencedirect.com/topics/neuroscience/2-3-bisphosphoglyceric-acid
(This makes sense when you look at the reaction here, because phosphate/Pi is bound in 2,3-DPG. This reaction can go in both directions and is a chemical equilibrium, so the body tries to keep the concentrations of the involved substances stable by shifting the reaction. If phosphate is high, the body will increase the reaction to 2,3-DPG which binds phosphate in 2,3-DPG and reduces free phosphate like that.)

High phosphate can cause high 2,3-DPG, but I wouldn't really know why/if you might have high phosphate. I think some severe cause would be unlikely, maybe it could somehow be related to the existing metabolic problems/metabolic balance?

It is a bit eye-catching that some important metabolic processes lead to increased phosphate binding.
The respiratory chain binds phosphate to ADP (ADP+Pi->ATP) and creatine (synthesis uses SAMe) to creatinephosphate (pathway here).
Some other processes that use phosphate are phospholipid synthesis, synthesis of other nucleic acids (UTP, CTP,..) and phosphate can act as a buffer, although I don't see yet how that would fit.
Don't know if low function of some of these pathways might increase unbound phosphate.

 

[PinkPanda]

https://forums.phoenixrising.me/index.php?attachments/blood-gas-results-jpg.21391/
These test results are weird though, or maybe I'm getting it wrong?

Superficial venous plasma pH decreased progressively to reach 7.1 +-0.003 at the end of the fourth exercise period and remained low during recovery

Plasma HCO3- decreased progressively to reach 10mmol/l following the fourth exercise period and remained below 12mmol/l for the next 20 min of recovery.

Plasma lactate concentration (La-) increased to 6.8 +- 1.11mmol/l (Fig.4) and continued to rise until 3 min of recovery following the third exercise period when a plateau was reached between 21 mmol/l and 23mmol/l. Plasma (La-) remained above 20 mmol/l for 10min during recovery following the fourth exercise period and fell to 17.3 +- 0.99 mmol/l following 20 min of recovery.

https://www.researchgate.net/public...d_metabolism_in_maximal_intermittent_exercise

I think the ranges and measurement methods are different, and the numbers exact numbers can’t be compared.

As exercise intensity continues to increase, eventually reaching or exceeding 55% to 65% of maximal aerobic capacity, the increased ventilation is more related to the physiological need of carbon dioxide elimination rather than oxygen consumption. This ‘break point’ at which a disproportionate increase in ventilation and carbon dioxide production occurs,..

With the rate of lactic acid production exceeding the lactic acid removal rate, buffering of lactic acid becomes imperative to maintain homeostasis. The buffering of lactic acid through the bicarbonate system yields non-metabolically produced carbon dioxide, as indicated in the following chemical reaction:

La- + H+ + NaHCO3- -> NaLa + H2CO3
Lactic acid + sodium bicarbonate yields sodium lactate + carbonic acid.

H2CO3 -> H2O + CO2

Carbonic acid rapidly dissociates, yielding carbon dioxide and water.

The resulting effect is much more rapid production of carbon dioxide in the cardiovascular system, as carbon dioxide is produced both metabolically and nonmetabolically through lactic acid buffering.

Exercise and Sport Science p.126

So I think during anaerobic exercise (into the recovery phase) lactate should rise, pH should decrease/ more acidic,
and carbon dioxide should rise, or at least not fall. Carbon dioxide production rises during exercise as does breathing it off, I don't know how much the blood level rises, but it shouldn't drop.

Your lactate rises, which confirms that you have gone into anaerobic respiration, but your pH also rises/less acidic and your CO2 drops. pH should drop, if lactate rises, or at least not rise.

Maybe this really speaks for an under-production of protons in the recovery phase of exercise (->Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome), which also reduces CO2 through less conversion from bicarbonate (H+ + HCO3- -> H2CO3 -> CO2 + H2O)
and too low citric acid cycle function that reduces proton and CO2 (metabolically produced) production in ME/CFS? Especially, when you go into anaerobic metabolism.

Maybe the produced protons in the energy processes inside the cell actually do come into the blood and lower blood pH and if they are being underproduced, blood pH doesn't sink as it should?

 

[kangaSue]

@Valentijn Have you tried an arginine or citrulline supplement before for the impaired blood perfusion in microvasculature that can lead to lactic acidosis, among other things things?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519148/