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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.
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
http://derangedphysiology.com/main/core-topics-intensive-care/arterial-blood-gas-interpretation/Chapter 4.0.5/factors-which-influence-affinity-haemoglobin-oxygenThe 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://www.jbc.org/content/279/43/44976.fullApplication 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).
https://en.wikipedia.org/wiki/Calcium_release_activated_channelThe 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/SOC_channelsStore-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://www.sciencedirect.com/topics/neuroscience/2-3-bisphosphoglyceric-acidAn 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.researchgate.net/public...d_metabolism_in_maximal_intermittent_exerciseSuperficial 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.
Exercise and Sport Science p.126As 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.