RT Journal Article
SR Electronic
T1 Acidic pH is a Metabolic Switch for 2-Hydroxyglutarate Generation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 051599
DO 10.1101/051599
A1 Sergiy M. Nadtochiy
A1 James Miller
A1 Xenia Schafer
A1 Dragony Fu
A1 Keith W. Nehrke
A1 Joshua Munger
A1 Paul S. Brookes
YR 2016
UL http://biorxiv.org/content/early/2016/05/03/051599.abstract
AB 2-hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The D (R) enantiomer (D-2-HG) is an oncometabolite generated from α-ketoglutarate (α-KG) by mutant isocitrate dehydrogenase (ICDH), while L (S) 2-HG is generated by lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in response to hypoxia. Since acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may also impact cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate α-KG levels further stimulated this elevation. Studies with isolated LDH-1 and MDH-2 revealed that generation of 2-HG by both enzymes was stimulated several-fold at acidic pH, relative to normal physiologic pH. Furthermore, acidic pH was found to inhibit the activity of the mitochondrial L-2-HG removal enzyme L-2-HG dehydrogenase. We conclude that acidosis is an important and previously overlooked regulator of 2-HG levels, with implications for 2-HG signaling.