Lactate: the ugly duckling of energy metabolism, 2020, Rabinowitz and Enerbäck

[SNT Gatchaman]

Lactate: the ugly duckling of energy metabolism
Rabinowitz JD, Enerbäck S

Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals.

Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate's reputation as a deleterious waste product.

In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues.

This reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen's ugly duckling is actually a beautiful swan-has the potential to reshape the field of energy metabolism.

PubMed Link | PubMed PDF | Nature Metabolism PDF

 

[Hutan]

I've just started to read this. I thought this was interesting - cultured cells don't behave like cell in vivo with respect to lactate production. Possible reasons are the formulation of the growing media and the fact that feedback mechanisms that would affect the cell in vivo are not present.

Lactate production does not occur in only oxygen-limited muscle. Most cultured mammalian cells produce copious lactate even when oxygen is abundant. Such aerobic glycolysis was initially noted by Warburg nearly a century ago, and rapid lactate production was the first molecular phenotype associated with cancer6. This observation led to the hypothesis that cancer is a disease of defective mitochondria7. But although mitochondrial defects occasionally occur in cancer, they are not a major cause8-10. Instead, fermentation is a common feature of mammalian cells in culture, including non-cancerous cells, such as proliferating T cells and even non-growing cells, such as quiescent fibroblasts11,12.

The reasons why cultured cells avidly ferment glucose remain incompletely understood, but media formulation plays a role. Classical tissue medium contains serum growth factors, supraphysiologic glucose and no lactate13. In such conditions, glucose is the only available carbohydrate fuel. Moreover, both glucose availability and lactate secretion are unconstrained, and glucose is refreshed and lactate is removed every time the culture medium is changed. These factors, together with growth-factor signals that trigger glucose uptake14, favour avid glucose fermentation. The release of lactate by both cells in vitro and stressed muscle in vivo supports the paradigm of glucose as fuel and lactate as waste.

 

[SNT Gatchaman]

I've read it through and while it would probably take another couple of runs to better follow the detail, the overview seems potentially quite relevant. (It fortuitously came up on my Twitter feed via Nature Metabolism's "throwback Thursday".) A few high-level quotes that caught my eye —

In the absence of lactate, glycolysis must operate in lockstep with the TCA cycle, such that every glycolysis-produced NADH and pyruvate is cleared by mitochondrial metabolism. Correspondingly, cells would need to break down glucose via glycolysis to generate energy from carbohydrate. Lactate’s fundamental role is to uncouple these pathways.

Despite [pyruvate dehydrogenase kinase]'s importance, manifested by the existence of four different kinase isozymes, its physiological purpose remains unclear.

Given the particularly tight control of circulating lactate levels, a novel regulatory system for lactate homeostasis is likely to exist.

Circulating lactate can also enter the faeces and thereby feed the microbiome. A quantitative understanding of the importance and regulation of microbiome-mediated lactate clearance merits further investigation.

Also, having reported PET scans for over 10 years, I enjoyed stopping for a moment to think about something that is fundamental to the technique, but which we don't tend to think about the underlying nature of —

In agreement with glucose use being relatively restricted, fluoro-deoxyglucose positron emission tomography (PET) imaging studies show intense glucose uptake in the brain, tumours and areas of inflammation, but little uptake in many other parts of the body. Although this finding partially reflects PET imaging studies being conducted in fasted resting individuals, the PET data align with glucose-transporter expression, which is strongest in the brain and activated immune cells.

 

[Mithriel]

The more they work out how energy is produced the closer they will be to finding the cause of ME. Vice versa, studying ME may give them insight into energy production by looking at our symptoms.

I get a deep, acid burning in my muscles if they are overused. Some process has gone wrong.

 

[DokaGirl]

The more they work out how energy is produced the closer they will be to finding the cause of ME. Vice versa, studying ME may give them insight into energy production by looking at our symptoms.

I get a deep, acid burning in my muscles if they are overused. Some process has gone wrong.

Agreed.

The article says lactate production increases when demand for ATP and oxygen are in short supply. My legs become very painful, when climbing stairs and small hills. So not after a run, just a bit of normal walking. In PEM, my legs can be very painful just walking on the main floor of my house.

If science understands at least some of the mechanism of lactate versus ATP and oxygen, it would very good if there could be more study focused on how this goes wrong in ME.

I'm also wondering if this is somehow tied up with RBCs, and blood circulation studies in ME.

When I was quite anemic, the fatigue, palpitations, shortness of breath, and leg pain became even more pronounced. I had more frequent crashes, and spent even more time couch ridden. At one point I couldn't walk across one room without needing to rest due to leg pain and shortness of breath.

My hemoglobin had been tested, and was good, which supposedly ruled out iron deficiency. However, a later test revealed ferritin in the iron deficiency range.

We get these brief glimmers of insight into ME. It would be wonderful if researchers could piece it all together.