Hypoxia As A Therapy For Mitochondrial Disease

paymanz

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Hypoxia as a therapy for mitochondrial disease. - PubMed - NCBI

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.

Finally, it is notable that the aging process and virtually
all age-related degenerative diseases are associated with
secondary mitochondrial dysfunction and oxidative stress
(40). While antioxidants have been proposed as a strategy to
alleviate these disorders by scavenging free radicals, our
work suggests that simply limiting the substrate for oxygen
toxicity may prove more effective
.
http://www.sciencemag.org/news/2016...tm_medium=twitter&utm_campaign=oxygendep-2589

It was a gene called the von Hippel-Lindau (VHL) factor, which encodes a protein that puts a brake on the cellular hypoxia response. Deactivating the VHL gene makes animals react as if they’re in a low-oxygen environment, also called hypoxia.

In zebrafish with dysfunctional mitochondria, shutting down VHL nearly doubled their lifespan, Jain’s team discovered. They then moved to mice with a version of a human mitochondrial disease called Leigh syndrome. The researchers kept the animals in chronically thin air that’s similar to the oxygen levels people would experience at the peak of Mont Blanc, the tallest mountain in the Alps, which soars nearly 5000 meters above sea level. The hypoxia-treated rodents lived more than 6 months, compared with about 2 months for untreated animals,Mootha and his colleagues report online today in Science. “The results were far more striking than we hoped,” he says.

while hypoxia inhibits the production of much-needed ATP, it also blunts production of free radicals, harmful molecules that can damage tissues and may cause problems in children with mitochondrial diseases. Another the group is considering is that hypoxia activates alternative ATP production pathways that help the organism function normally.
 
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paymanz

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@jyb what they did to rodents, they simulated high altitude. ray also recommends it , high altitude or low oxygen pressure.

Another the group is considering is that hypoxia activates alternative ATP production pathways that help the organism function normally.
 

jyb

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@jyb what they did to rodents, they simulated high altitude. ray also recommends it , high altitude or low oxygen pressure.

Ok but there is a difference between higher altitude and CO2, and extreme altitude to the point of ATP reduction (the quote you inserted should take that into account). At least, I wonder...
 

paymanz

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i dont know when co2 production is low , what happens to oxygen in lungs, does it get into blood and in the form of free oxygen?!,,if yes then it can be a cause of free radicals .... other than antioxidant properties of co2.
 

paymanz

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@jyb when there is less oxygen available , there is less rate of exchange of oxygen with co2,and that causes loss of co2.my understanding.
 

paymanz

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i like to know peat's opinion on this:

from same study said:
hypoxia leads to a state in which oxygen delivery
and consumption are simultaneously reduced, whereas in
mitochondrial disease, oxygen delivery continues in the face
of impaired utilization. Such a mismatch between delivery
and utilization, potentially contributes to oxygen toxicity
 
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The point is having less oxygen pressure to steal carbon dioxide from you...
 

Amazoniac

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Protective effects of intermittent hypoxic adaptation on myocardium and its mechanisms. - PubMed - NCBI

"Chronic continuous hypoxic adaptation is associated with a variety of adaptive changes at the level of myocardial energy production and utilization that enable the heart to work more economically and thus can protect the myocardium from the lack of oxygen. According to Moret [1], these changes may involve an increased capacity of aerobic metabolism, as indicated by the larger number of mitochondria, as well as enhanced activities of certain mitochondrial enzymes or cytochromes, an improved ability of mitochondria-generated energy in the presence of low ADP concentrations, greater efficiency of oxidative phosphorylation, and preferential use of the carbohydrates as substrate. An increased glycolytic capacity is also implied in the protective effect of acclimatization to high-altitude continuous hypoxia [15]. Chronic hypoxia decreases the specific activities of several sarcolemmal [had to look up, from Wikipedia: "is the cell membrane of a striated muscle fiber cell"] ATPases in the myocardium, and also increases their affinity for ATP [16]. This may elevate the efficiency of available ATP utilization and therefore help preserve membrane transport functions under conditions of low energy production."

"The reduction in oxygen consumption in the hearts of humans and animals undergoing continuous or intermittent hypoxic adaptation, as compared to control hearts [7], also supports the more efficient energy metabolic system being involved in the cardioprotective effects of intermittent hypoxic adaptation."

"They showed that 4 weeks of interval hypoxic training lowered the heart rates and ventilation at submaximal workloads, without, however, diminishing maximum heart rates and performance."

"Endogenous antioxidant systems, such as superoxide dismutase and catalase, prevent the activation of the lipid perioxidant chain reaction and thus enhance the resistance of the myocardium to ischemia- or hypoxia-induced injury. Reoxygenation, rather than hypoxia, facilitates the generation of oxygen-derived free radicals. Because the apparent difference between continuous and intermittent hypoxic adaptation is the adaptive course of the latter, not only as a hypoxic session by itself but also being separated by several reoxygenation sessions, it is attractive to speculate that the reoxygenation sessions of intermittent hypoxic adaptation boost antioxidant generation in the cardiac tissue, and therefore protect the myocardium from later injury caused by oxygen-derived free radicals. Experimental evidence provided by Meerson [7] indicates that continuous hypoxia decreases the activity of the principal antioxidant enzymes in the heart, while intermittent hypoxia increases the enzymes."

"However, the different responses of antioxidants to continuous and intermittent hypoxic adaptation are definite, according to Meerson’s [24] description. Increased antioxidant activity induced by intermittent hypoxic adaptation seems to be more involved in the protection of other organs like brain and liver."

"Acute hypoxia significantly increases the production of prostaglandins in the myocardium [30]. With prolonged stay at a high altitude of 4,350 m, however, the plasma levels of those substances in humans return to control values after 8 days [31]. Intermittent hypoxic adaptation to a similar altitude (hypobaric-chamber-simulated) elevated the levels of prostaglandins in the myocardium of rats, remaining high even after 40 days of acclimatization [32]."
 

ddjd

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superoxide dismutase and catalase, prevent the activation of the lipid perioxidant chain reaction and thus enhance the resistance of the myocardium to ischemia- or hypoxia-induced injury
is it worth supplementing SOD?
 

yerrag

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@paymanz I can relate to hypoxia being beneficial to me. I believe that the kidney's angiotensin-renin system, which is responsible for the constriction and dilation of blood vessels, is doing the job of creating hypoxic conditions. And it's important that the kidney is assigned the task, because a well-functioning kidney is so important to acid-base regulation in the blood, which affects the quality of our metabolism, and is a major determinant of our general health. Couple with that the fact that the kidney is the organ that has the most to lose, as it is an organ that can easily get destroyed by oxidative stresses, for which no recourse is possible once tissue is destroyed, as it's generally accepted that kidney tissues are difficult, if not impossible to regenerate. My experience with high blood pressure centers on the need for the kidneys to generate more uric acid to protect my kidneys from lead toxicity, and hypoxia is an enabler for uric acid production. Lead is embedded in the mitochondria of the tubules of my kidney. The mitochondria is not fully functional, and this is affecting the resorption of albumin back into my blood. I think this has to do with the mitochondria not having enough energy to allow the resorption of albumin, and this has a lot to do with the charge a fully functional mitochondria is able to produce, which would attract the albumin in the process of resorption. My detox protocols involves using Vitamin C and magnesium to chelate lead from the kidneys. I believe that in restoring magnesium from deficiency to normalcy in the body would help produce energy that would enable magnesium to displace to lead embedded in the kidney tubules' mitochondria. I currently have a log in this forum which details my progress.

If hypoxia's role is appreciated more, and if it is closely associated with high blood pressure, I believe people will begin to appreciate the role of its manifestation in hypertension in a more positive way. Instead of seeing high blood pressure as an evil categorically, one would have to see certain instances of hypertension as a beneficial response to a pathological condition, the benefit being that it protects the body from further destruction from a pathological state. In my case, it is lead toxicity. But there are many other causes such as infection and plaques. The current approach of making people take antihypertensive drugs is precisely the wrong thing to do. It is taking away the protection from further tissue destruction that underlies the mechanism by which hypertension is created. Mainstream medical dogma has inculcated in the general population the fear of a future ruptured vessel or the fear of kidney damage that makes people commit self-mutilation internally through the use of antihypertensive drugs without question.

Hypertension should be seen in the same light as fever. We accept the healing nature of a fever, but we can never accept the coping and amelioratory function of hypertension. There is a double standard going on here.
 
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Evgenius

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@paymanz I can relate to hypoxia being beneficial to me. I believe that the kidney's angiotensin-renin system, which is responsible for the constriction and dilation of blood vessels, is doing the job of creating hypoxic conditions. And it's important that the kidney is assigned the task, because a well-functioning kidney is so important to acid-base regulation in the blood, which affects the quality of our metabolism, and is a major determinant of our general health. Couple with that the fact that the kidney is the organ that has the most to lose, as it is an organ that can easily get destroyed by oxidative stresses, for which no recourse is possible once tissue is destroyed, as it's generally accepted that kidney tissues are difficult, if not impossible to regenerate. My experience with high blood pressure centers on the need for the kidneys to generate more uric acid to protect my kidneys from lead toxicity, and hypoxia is an enabler for uric acid production. Lead is embedded in the mitochondria of the tubules of my kidney. The mitochondria is not fully functional, and this is affecting the resorption of albumin back into my blood. I think this has to do with the mitochondria not having enough energy to allow the resorption of albumin, and this has a lot to do with the charge a fully functional mitochondria is able to produce, which would attract the albumin in the process of resorption. My detox protocols involves using Vitamin C and magnesium to chelate lead from the kidneys. I believe that in restoring magnesium from deficiency to normalcy in the body would help produce energy that would enable magnesium to displace to lead embedded in the kidney tubules' mitochondria. I currently have a log in this forum which details my progress.

If hypoxia's role is appreciated more, and if it is closely associated with high blood pressure, I believe people will begin to appreciate the role of its manifestation in hypertension in a more positive way. Instead of seeing high blood pressure as an evil categorically, one would have to see certain instances of hypertension as a beneficial response to a pathological condition, the benefit being that it protects the body from further destruction from a pathological state. In my case, it is lead toxicity. But there are many other causes such as infection and plaques. The current approach of making people take antihypertensive drugs is precisely the wrong thing to do. It is taking away the protection from further tissue destruction that underlies the mechanism by which hypertension is created. Mainstream medical dogma has inculcated in the general population the fear of a future ruptured vessel or the fear of kidney damage that makes people commit self-mutilation internally through the use of antihypertensive drugs without question.

Hypertension should be seen in the same light as fever. We accept the healing nature of a fever, but we can never accept the coping and amelioratory function of hypertension. There is a double standard going on here.

Have you tried kidney glandular in attempt to regenerate them ?
 

yerrag

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Evgenius

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I haven't. What is your experience with it.
With kidney none, but I have experience with other glandular extracts (adrenal, thyroid, thymus etc.) and think they are worth considering if you have problem with regenerating and strengthening a particular gland.
 

yerrag

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With kidney none, but I have experience with other glandular extracts (adrenal, thyroid, thymus etc.) and think they are worth considering if you have problem with regenerating and strengthening a particular gland.
Thanks. That would be helpful.
 
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