Friday, August 21, 2020

More lactate wars

I have a suspicion that lactate as a portable energy source might be going to become quite interesting. I'll hit publish on this post which has been lying around on the draft list for some time. Here goes.

Some groups of researchers have been interested in lactate as a fuel for oxidative metabolism for a very long time. My own biases rather like this approach, so beware.

Back in 2008 we have this paper:

Mitochondrial Lactate Dehydrogenase Is Involved in Oxidative-Energy Metabolism in Human Astrocytoma Cells (CCF-STTG1)

"Taken together, this study implicates lactate as an important contributor to ATP metabolism in the brain, a finding that may significantly change our notion of how this important organ manipulates its energy budget."

which is clearly preposterous if you are part of Fulghum's group in Kentucky. From 2019:

Mitochondria-associated lactate dehydrogenase is not a biologically significant contributor to bioenergetic function in murine striated muscle

"We find that cardiac mitochondria do not contain LDH ... These results indicate that cytosolic, and not mitochondrial, LDH promotes cardiac lactate oxidation."

"Our findings show negligible levels of lactate oxidation in isolated mitochondria from heart and skeletal muscle in sedentary, acutely exercised, and exercise-adapted conditions."

A finding which was promptly addressed in 2020 by Mailloux, now in Canada:

Lactate dehydrogenase supports lactate oxidation in mitochondria isolated from different mouse tissues

"Using the guide supplied by Passarella et al., we counter the conclusions drawn by Fulghum et al. and demonstrate that mitochondria oxidize lactate."

"Collectively, we can conclude lactate is a good fuel for mitochondrial bioenergetics in mammalian cells."

This is clearly an ongoing battleground and I doubt the exchange of half bricks is finished yet. It certainly brings to mind the astrocyte-neuron lactate shuttle

Lactate: the ultimate cerebral oxidative energy substrate?

which has largely been destroyed by

Control of brain energy supply by astrocytes

which I had a think about in this post. I do wonder if this declaration of destruction might be a little premature too. As was said in the Monty Python sketch: "I'm not dead yet!".

Ultimately, isolated mitochondria are very, very far away from anything physiological. I get the impression that the conditions they are studied under are utterly critical for the results you might like to get, or not get. The models are not useless per se but anything found needs to be considered very carefully, often in the absence of knowledge about what does and doesn't matter within the methods section and which may well have been tweaked to get the result desired. And in the context of what might be published next year.

I think abandoning lactate as a super-fuel might be a little premature. Beware of my biases.



karl said...

Just read a bunch of people talking about Meldonium translated from Russian.

I'm fairly sure there is an important effect on the brain. Is lactate the key factor?

I don't expect to see any big population papers here in the west - not patentable - thus no research.

Serdna said...

I suppose it has something to do with lactate usefulness to the brain: Tassinari et alter, Lactate administration reduces brain injury and ameliorates behavioral outcomes following neonatal hypoxia-ischemia, 2020 (via Cecilia).