Today we posted a pre-print on BioRxiv for the first time. Here‘s the paper, entitled “Acidic pH is a Metabolic Switch for 2-Hydroxyglutarate Generation”. It reports pretty much what the title says!
A little background… 2-HG has been known about for quite some time as an “oncometabolite”, with the D enantiomer (D-2-HG) being made by mutant forms of isocitrate dehydrogenase found in various cancers.
However, that all changed last year with 2 back-to-back papers in Cell Metabolism from the labs of Craig Thompson & Joe Loscalzo, reporting that L-2-HG is made in response to hypoxia, by the enzymes lactate deydrogenase and malate dehydrogenase (side note – we also found 2-HG elevated in the ischemic heart as early as 2013, but were slow in publishing).
We’ve been messing around with 2-HG regulation for a while, and just sort of stumbled on the fact that the enzymes that make and degrade it are all sensitive to pH. This makes sense when you consider that acidic pH is a common feature of hypoxia, and it’s also found in the tumor micro-environment, so our results might also be relevant for cancer.
The other upshot – this work might be relevant for a set of devastating metabolic diseases, the 2-hydroxyglutaric-acidurias. These often co-present with lactic acidosis, so it’s possible that lactic acid crises may be precipitating events. This suggests that careful management of pH in these patients (e.g. using dichloroacetate to drive PDH activity) might be therapeutically beneficial.
The work is currently churning its way through the regular journal peer review system, but you’ll see if you read the paper that the experiments are actually pretty simple. As such, we thought the results might be particularly “scoop-worthy”, and so that drove the decision to post a pre-print.
This was our first time posting on BiRxiv (kinda like our most recent paper was the first time we posted a complete underlying data set on FigShare). Both processes were completely intuitive and painless. I’m beginning to like this open science game!