Mitochondrial Uncoupling

noqcks

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Hey everyone. I've seen the term "uncoupling" used around the forum. I'd like to share what I've learned about Mitochondrial Uncoupling. I also have a few questions.

From one of rays articles

Uncoupling--In cellular respiration, oxidation of "fuel" in the mitochondrion is coupled to the phosphorylation of ADP, forming ATP. Uncouplers are chemicals that allow oxidation to proceed without producing the usual amount of ATP.​

I'm going to assume basic understand of mitochondria morphology and oxidative phosphorylation.

In the Electron Transport Chain (ETC), protons (H+) move from the mitochondrial matrix to the intermembrane space via the different ETC complexes (I, II, II, IV). The intermebrane space contains a higher concentration of H+ ions than the matrix — a concentration gradient is created, this is also sometimes referred to as the "proton-motive" force. There is an energy potential in the difference between these two concentrations that can be utilized. You can see all this happening in Figure 1.

Figure 1.
J6cRPmj.png

The H+ ions need to be moved back into the Matrix so that they can be re-used by the Electron Transport Chain. The H+ ions can move back into the matrix from the intermembrane space in one of two ways.

  1. via ATP synthase. This enzyme uses ADP in the matrix and energy potential from the H+ gradient to produce ATP. Thus it is said that oxidative phosphorylation is coupled to the phosphorylation of ADP to produce ATP with ATP synthase. It is the limiting factor.

  2. via uncoupler proteins. Instead of ATPase, which needs ADP in the Matrix space to function, uncoupling proteins can be used to shuttle H+ across the membrane. This produces some heat in the process. I think higher body temps is what most people refer to when describing "uncoupling effects". It results in higher oxygen consumption, C02 production, lower lactate formation, and increases whole body energy expenditure. You can see the uncoupler protein in Figure 2. When using an uncoupler protein, respiration (oxidative phosphorylation) is said to be uncoupled.
Figure 2.
3Nz9R3Q.png


You can see in Figure 3, for example, what oxygen concentration looks like when an 2,4-Dinitophenol is used, an agent used for uncoupling oxidative phosphorylation.

Figure 3.
0UJMA2h.png


Some quotes from Peat

Aspirin and thyroid (T3) increase uncoupling. A drug that used to be used for weight reduction, DNP, also uncouples mitochondrial metabolism, and, surprisingly, it has some of the beneficial effects of thyroid and aspirin. It stimulates the consumption of lactic acid and the formation of carbon dioxide.

The squirrel monkey, which on average weighs about 2 or 3 pounds as an adult, lives much longer than other mammals of its size, usually about 20 years, as long as 27. It has an extremely high rate of oxygen consumption. This is probably the result of natural uncoupling of the mitochondria, similar to that seen in long-lived mice. Mice with 17% higher resting oxygen consumption lived 36% longer than slow respiring mice of a related strain (Speakman, et al., 2004).
When mitochondria are “uncoupled,” they produce more carbon dioxide than normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.


Questions I have for the smart people around here:
- How exactly does it reduce lactate production?
- Why is excessive uncoupling seen in cancer cells?
 
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Hans

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For the first question, my guess is that it lowers lactate, by lowering pyruvate. More pyruvate is used in the Kreb cycle, so less is left for LDH. Also, the CO2 produced through uncoupling inhibits lactate production.

For the second question, the brown fat mostly uncouples (about 90%) and an excess of brown fat could theoretically lead to wasting. In terms of cancer, the mitochondria should balance ATP production and uncoupling. If there is adequate ATP, the mitochondria can uncouple. But the mitochondria should not uncouple if there is insufficient ATP. I think this might be what's happening in cancer cells. Also, there are two different kinds of uncoupling - "induced" uncoupling through UCPs which is controlled, and passive proton leak which is not controlled. Passive proton leak is induced by a too fluid membrane (PUFAs do this), which is what's happening in cancer is my guess.
In summary, cancer cells generate most of their energy from anaerobic glycolysis and not through oxidative phosphorylation. Thus, instead of creating ATP (perhaps because the ATPase is broken or cardiolipin is oxidized), the ETC supports/drives uncoupling. Another possibility is that the UCPs are attempting to rescue cellular function by boosting CO2, lowering lactate and eliminating PUFAs.
Disclaimer, the reason why I'm making a few guesses is because I have researched uncoupling, but not extensively in the context with cancer.
 
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noqcks

noqcks

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Awesome thanks Hans. I had no idea about the passive proton leak.

It looks like indeed passive proton leak is much higher in cancerous cells, which should account for their increased uncoupling.

Proton leak or back-decay (smaller thin arrow) is greater in mitochondria of tumor cells than in mitochondria of normal cells

Cancer as a Metabolic Disease, pg 51
 

Hans

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Awesome thanks Hans. I had no idea about the passive proton leak.

It looks like indeed passive proton leak is much higher in cancerous cells, which should account for their increased uncoupling.



Cancer as a Metabolic Disease, pg 51
I forgot to mention, cancer cells upregulate uncoupling proteins to protect themselves against ROS and lipid peroxidation. So it's a defense mechanism, since ROS and lipid peroxidation can destroy cells (cancer cells don't want to die. They're considered immortal cells). Cortisol is also able to induce uncoupling, which is obviously not what you want, if it's in excess chronically.
 

Mauritio

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Wouldnt it be beneficial if we boost atp synthase somehow, since it would yield more atp ?
 
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S-VV

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The generation of lactic acid is tied to the redox state of the catabolic NAD+/NADH pair. In glycolysis, glucose is converted to pyruvate, and in this process it is oxidised two times, converting two NAD+ to two NADH. These oxidations are necessary enzymatic steps, without which the conversion cannot continue. When the ETC stalls, the Krebs cycle stalls, and pyruvate, instead of being decarboxylated, combined with oxaloacetate to form citrate and feed the cycle, hangs aorund in the cytoplasm. The cell then is forced to use only glycolysis as the energy source, since glycolysis actually generates 2 ATP. The problem is that the generated NADH are still reduced, since the ETC , the usual oxidiser, is not working, and due to reaction kinetics, the more NADH, the slower glycolysis occurs. The solution is to reduce pyruvate to lactate, gaining back NAD+ to ensure a high glycolytic flux.

An alternative is to "force" the ETC to move, and assuming enough oxygen is present to be the final electron acceptor, by dissipating the H+ gradient you activate the four mitochondrial complexes, the first one using NADH to pump the protons, and giving back NAD+, preventing the need to reduce pyruvate to lactate. Of course, if the lactic acidosis is due to hypoxia, you will make things worse.
 

gaze

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For the first question, my guess is that it lowers lactate, by lowering pyruvate. More pyruvate is used in the Kreb cycle, so less is left for LDH. Also, the CO2 produced through uncoupling inhibits lactate production.

For the second question, the brown fat mostly uncouples (about 90%) and an excess of brown fat could theoretically lead to wasting. In terms of cancer, the mitochondria should balance ATP production and uncoupling. If there is adequate ATP, the mitochondria can uncouple. But the mitochondria should not uncouple if there is insufficient ATP. I think this might be what's happening in cancer cells. Also, there are two different kinds of uncoupling - "induced" uncoupling through UCPs which is controlled, and passive proton leak which is not controlled. Passive proton leak is induced by a too fluid membrane (PUFAs do this), which is what's happening in cancer is my guess.
In summary, cancer cells generate most of their energy from anaerobic glycolysis and not through oxidative phosphorylation. Thus, instead of creating ATP (perhaps because the ATPase is broken or cardiolipin is oxidized), the ETC supports/drives uncoupling. Another possibility is that the UCPs are attempting to rescue cellular function by boosting CO2, lowering lactate and eliminating PUFAs.
Disclaimer, the reason why I'm making a few guesses is because I have researched uncoupling, but not extensively in the context with cancer.
What would be the most practical things to decrease the "wasting" effect and high lactate? I know all the peaty things, but in terms of emphasis, should one have to increase ATP first, and then use more of the uncouples? Or uncoupling in a peat fashion does both at the same time by first producing enough ATP then uncoupling. I would assume in a wasting condition metabolic efficiency is of the highest priority, but I'm just confused if an "uncoupler" by definition produces all the ATP that is required by the body and then uncouples. So for someone who has a high need for ATP, pufa deficiency will first satisfy that need and then move on to producing more co2? But for someone with cancer, would a pufa deicifncy with not enough b vitamins cause more lactate or less than an ordinary diet with pufa?
 
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Hans

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What would be the most practical things to decrease the "wasting" effect and high lactate? I know all the peaty things, but in terms of emphasis, should one have to increase ATP first, and then use more of the uncouples? Or uncoupling in a peat fashion does both at the same time by first producing enough ATP then uncoupling. I would assume in a wasting condition metabolic efficiency is of the highest priority, but I'm just confused if an "uncoupler" by definition produces all the ATP that is required by the body and then uncouples. So for someone who has a high need for ATP, pufa deficiency will first satisfy that need and then move on to producing more co2? But for someone with cancer, would a pufa deicifncy with not enough b vitamins cause more lactate or less than an ordinary diet with pufa?
Sodium bicarb, vitamin B1 (combined with the other B-vitamins), magnesium, methylene blue and quinones would be highly effective for lowering and buffering lactate and promoting energy production.
A lot of Peat things, such as calcium, saturated fat, thyroid, aspirin, progesterone, etc., promote energy production and uncoupling.
 

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