Metabolism reprogrammed by the nitric oxide signalling molecule

Andy · Dec 5, 2018

Acute kidney injury can lead to chronic renal failure, which causes fluid and electrolyte imbalances in the blood that require dialysis. Such injuries commonly involve ischaemia–reperfusion events, in which the blood supply to the kidney is temporarily restricted but then restored; this process generates toxic oxygen radicals that can cause renal inflammation and damage. Writing in Nature, Zhou et al.1 report that the signalling molecule nitric oxide2,3 reprograms a metabolic pathway, and thereby limits ischaemic injury and protects renal function.

Read the paper: Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury

Nitric oxide is synthesized by a family of enzymes called nitric oxide synthases (NOS), which fall into three groups: neuronal NOS, inducible NOS and endothelial NOS (eNOS). The molecule signals through several distinct mechanisms4. For example, it can interact with transition metals such as those in the haem group of guanylyl cyclase enzymes, which produce cyclic GMP — a messenger molecule involved in many biological processes. It can also combine with oxygen molecules to produce reactive nitrogen oxide species that, in turn, react with cysteine amino-acid residues on target proteins5, forming modifications called S-nitrosothiols. Nitric oxide regulates a variety of physiological processes, including dilation of blood vessels (vasodilation), communication between neurons and the killing of disease-causing agents by the immune system.
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https://www.nature.com/articles/d41586-018-07457-z

Hutan · Dec 5, 2018

This is an interesting paper.

The authors of the current study set out to identify the pathways by which nitric oxide protects against ischaemia. Using mass spectrometry, they discovered that one of the proteins most commonly modified by the molecule is pyruvate kinase M2, an enzyme that catalyses glycolysis (the metabolic pathway by which glucose is converted into energy). In a clever set of biochemical studies, they showed that nitric oxide modifies specific cysteine residues of pyruvate kinase M2. These modifications block the assembly of the active form of the enzyme, thereby inhibiting glycolysis. This is one of the key findings of the study: pyruvate kinase M2 is a target of nitric oxide.
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The researchers used a technique called metabolic profiling to show that the kidney cells of mice lacking pyruvate kinase have high levels of products of the pentose phosphate pathway12 — a metabolic pathway parallel to glycolysis that produces sugars called pentoses and the enzyme cofactor NADPH. NADPH acts in antioxidant systems to restore the function of proteins that have been damaged by oxidative stress in ischaemia13. The authors therefore conclude that nitric oxide inhibits pyruvate kinase and glycolysis, causing glucose levels to increase. The excess glucose spills over into the pentose phosphate pathway, generating high levels of NADPH, which shores up the antioxidant defences that limit renal injury (Fig. 1). This reprogramming of metabolism represents a major new aspect of nitric oxide biology.
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obeat · Dec 5, 2018

I think ME biobank are sending samples to an Austrian researcher investigating NOS?

Inara · Dec 5, 2018

That's indeed very interesting. Thank you @Andy for sharing.

Andy · Dec 5, 2018

obeat said: ↑

I think ME biobank are sending samples to an Austrian researcher investigating NOS?
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Well remembered, details in the tweets in this post, https://s4me.info/threads/updates-from-the-uk-me-cfs-biobank.2401/page-3#post-109236

sb4 · Dec 5, 2018

@Hutan Very interesting. So we could speculate that we probably don't have much problems with ischaemia as this lack of oxygen would also result in problems with fat metabolism. Quite a few people with CFS/POTS do ok on fats but bad on carbs. So what would be causing the NO that then results in poor PDH function?

Could it be some sort of pathogen or something in the gut? The body produces peroxynitrite to deal with pathogens, right?

Hutan · Dec 5, 2018

Ischaemia - an inadequate blood supply to an organ or part of the body

The work on blood cell deformability suggests that there is an inadequate supply of blood to some tissues due to problems with blood flow in the small capillaries.

I don't know. It would take me a long time to work out if/how this might fit with what we suspect about ME. But maybe someone who knows more can do it.

sb4 · Dec 5, 2018

@Hutan I do think there is a problem with blood getting places based on red cell deformity and my symptoms of pounding heart, feeling like it has to work harder to get the blood where it needs to be.

Having said this though, fat needs more oxygen to burn than carbs. So if we where experiencing a lot of ischaemia then I would think people would do a lot worse on fat but this doesn't seem to be the case generally. This sort of implies that if PDH malfunction is caused by NO then it is not generated by ischaemia but something else. Obviously just wildly speculating here.

Michelle · Dec 17, 2018

@sb4 : Of course, there is a subset of us ME/CFS patients who do have a lot of problems with fats (I know @Sid on the other forum has talked about her problems with fats also). I would think the patients with comorbid gastroparesis would be having difficulties with fats too as they slow down digestion.

Interesting study in light of some of the research going on, including Fluge and Mella's PDH paper a couple of years ago.

sb4 · Dec 15, 2018

@Michelle You are right about the gastropareses. In fact that is the reason I dont tolerate fats well. However the mechanism is differen't. As far as I am aware that actual metabolism of fat isn't a problem in as many people with CFS as is carb metabolism.

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Metabolism reprogrammed by the nitric oxide signalling molecule

Andy Committee Member

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Metabolism reprogrammed by the nitric oxide signalling molecule

Andy Committee Member

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Andy Committee Member

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Hutan Moderator Staff Member

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