The Metabolism Of Every Part Of The Body Is Affected By The Redox State Of The Blood

Mito

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The title is a sentence from Peat’s September 2020 newsletter. Here is the reference study.

The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes

Abstract
Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: β-hydroxybutyrate (βOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular βOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular βOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater βOHB/Acoc ratios were also associated with decreased β-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of βOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases.

The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes - PubMed
 

yerrag

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Exposure to a more oxidized ratio via extracellular βOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage.

On the other hand, addition of more reduced ratios of extracellular βOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes.

Can't understand these two statements. A more oxidized ratio is good. And a more reduced ratio is good also. Perhaps they could have worded it better? Or is that what they really mean?
 

Hans

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Can't understand these two statements. A more oxidized ratio is good. And a more reduced ratio is good also. Perhaps they could have worded it better? Or is that what they really mean?
A more oxidized state (e.g. higher NAD:NADH ratio) is superior to a reduced stated. Higher NADPH is found in cancer, whereas higher H2O2 production inhibits cancer progression. So an oxidized state is superior to a reduced state.
A reduced state increases gluconeogenesis and lipogenesis, which is famine and feasting signals combined. Both of which are elevated in diabetes. Again, not what you want.
Quinones (vitamin K2, thymoquinone, CoQ10, naphthoquinone, PQQ, etc.) and redox modulators such as methylene blue help to keep the cell in an oxidized healthy state.
 

yerrag

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Thanks Hans.

But what I don't understand is why a reduced state would result in a "maximal mitochondrial respiratory capacity in hepatocyles." Wouldn't it be more the case that the mitochondrial respiratory capacity would be reduced?

I'm also always confused about redox and get things mixed up. Would a more oxidized state go hand in hand with a reducing environment and a more reduced state go hand in hand with an oxidizing environment? And if so, would a reducing environment be alkaline and an oxidizing environment be acidic? And if so, would simply having good acid-base balance in the ecf be a good surrogate for the redox state in the ecf?
 

Hans

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But what I don't understand is why a reduced state would result in a "maximal mitochondrial respiratory capacity in hepatocyles." Wouldn't it be more the case that the mitochondrial respiratory capacity would be reduced?
NADH and FADH2 donates their hydrogens to complex I and II in the ETC, so more of them will "overload" the ETC. For example, too much FADH2 can cause a reverse electron flow and lead to electron leak and reactive oxygen specie generation.
I don't think the goal is to maximize mitochondrial respiratory capacity, because then there are a bigger risk of electron leak and ROS generation. Adding in methylene blue or quinones can help to remove the burden/bottleneck in the ETC. Redox modulator can also improve ATP and CO2 production because it removes the burden/bottleneck from complex I, II and III.
When ATP is sufficient, the body uncouples energy production.
And if so, would a reducing environment be alkaline and an oxidizing environment be acidic?
A reduced state would most likely have elevated lactate, which can make a cell too alkaline, as with cancer, whereas an oxidized state would have higher CO2 levels, making it resistant to cancer (R).
 

yerrag

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NADH and FADH2 donates their hydrogens to complex I and II in the ETC, so more of them will "overload" the ETC. For example, too much FADH2 can cause a reverse electron flow and lead to electron leak and reactive oxygen specie generation.
I don't think the goal is to maximize mitochondrial respiratory capacity, because then there are a bigger risk of electron leak and ROS generation. Adding in methylene blue or quinones can help to remove the burden/bottleneck in the ETC. Redox modulator can also improve ATP and CO2 production because it removes the burden/bottleneck from complex I, II and III.
When ATP is sufficient, the body uncouples energy production.

Too deep so far for me. But thanks for the explanation. Someday I'll be able to put this all together.

'm also always confused about redox and get things mixed up. Would a more oxidized state go hand in hand with a reducing environment and a more reduced state go hand in hand with an oxidizing environment? And if so, would a reducing environment be alkaline and an oxidizing environment be acidic? And if so, would simply having good acid-base balance in the ecf be a good surrogate for the redox state in the ecf?
I should change to this question :
Would a more oxidized state go hand in hand with an oxidizing environment and a more reduced state go hand in hand with a reducing environment? And if so, would an oxidizing environment be alkaline and an reducing environment be acidic? And if so, would simply having good acid-base balance in the ecf be a good surrogate for the redox state in the ecf?
 

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