Sunday, February 10, 2019

Cell surface oxygen consumption (3) Alternative options

Have a look at this:

Limits of aerobic metabolism in cancer cells

"To gain a better understanding of cell metabolism as a function of the growth metabolic demand we performed a back-of-the-envelope calculation focusing on the major biomass components of mammalian cells".

In these days of "shotgun metabolomics" two people appear to have sat down with one or more sheets of paper (possibly larger than an envelope, though you can get some quite large envelopes I guess) and have gone back to basic first principles. They then published in a Nature journal. I love this. I feel it rates alongside getting this image published in Cell Metabolism.

TLDR for the paper:

Glucose drops through glycolysis to lactate at a rate where ATP generation per minute massively outstrips that available from mitochondrial oxphos. In redox balance. It's fast.

Anabolism from glucose consumes pyruvate (and phosphoenolpyruvate) which then forbids the pyruvate -> lactate NAD+ regeneration step. This imposes a need to avoid or deal with a cellular NADH excess.

In the Cell surface oxygen consumption (2) post I hypothesised that the regeneration of NAD+ at the cell surface would be in direct proportion to anabolism derived from pyruvate (ie glucose/glycolysis anabolism), to maintain redox balance (ie get rid of excess NADH, cycling it back to NAD+). It is particularly a feature of highly glycolytic cancer cells.

These folks appear to be saying the same thing but looking at differing cellular techniques to avoid NADH cumulation.

There's lots of other good stuff in there too. Like the rate of mitochondrial ATP generation from HeLa cell mitochondria compared to that of normal cardiac myocyte mitochondria. The ATP production via oxphos is an order of magnitude greater in mitochondria from the cardiac myocytes.

Oh, and glutaminolysis as another NADH avoiding ploy. This is the quote:

"Glutamate can be converted to citrate via reductive carboxylation. In this pathway the NAD(P)H production by glutamate dehydrogenase is compensated by the reverse activity of the NAD(P) isocitrate dehydrogenase (Fig. 1). Glutamate can be taken from the medium or generated from glutamine by glutaminase. Interestingly, arginine and proline can be produced from glutamate with concomitant consumption of NADH (Fig. 4a). This could provide an additional mechanism for NADH turnover".

Note that the glutamate is not being oxidised, it is running a small section of the TCA backwards to generate citrate for lipid synthesis, ie anabolism. This is not glutamate turning the TCA in the normal direction toward oxaloacetate to generate ATP via NADH and oxphos, because the mitochondria of cancer cells don't seem to do oxphos very well. Somewhat Seyfried supportive.


1 comment:

Passthecream said...

Nice paper. I will print myself a copy for slow contemplation in the hope that I'll understand some of it!

'Note that the glutamate is not being oxidised, it is running a small section of the TCA backwards to generate citrate for lipid synthesis, ie anabolism. '

This is strongly reminiscent of the truncated TCA in hepatocytes due to physiological Salicylate shown in the paper I mentioned recently ( ). See in their first diagram that salicylate inhibits the TCA before the KGDH step likewise decreasing production of NADH.

They refer to an older paper dealing with truncated TCA under high energy demand Kondrashova, M.N. 1989, abstract at

The claim is that the slower part of the TCA is being side-stepped. Makes sense.

Wikip. informs me that deamination of glutamate by GDH is a method of dealing with excess nitrogen, converting it to ammonia which is further processed to Urea in the liver. Reminds me of the aspirin/gout connection.

High salicylate fruit, anyone?