Abstract
D-2-hydroxyglutaric aciduria is a rare inborn error of human metabolism caused by loss-of-function mutations in D-2-hydroxyglutarate(D-2HG) dehydrogenase (D2HGDH) resulting in the accumulation of D-2HG1. D-2HG inhibits multiple metabolic enzymes2-4 and promotes tumorigenesis5,6, however the endogenous metabolism of D-2HG remains poorly understood. Here, we find that, in the nematode Caenorhabditis elegans, the propionate shunt enzyme HPHD-17 produces D-2HG in a reaction coupled to oxidation of 3-hydroxypropionate (3HP), and that the D-2HG dehydrogenase DHGD-1 recycles D-2HG to α−ketoglutarate (αKG). dhgd-1 deletion mutants exhibit embryonic lethality, which can be rescued by vitamin B12 supplementation or by hphd-1 RNAi. Remarkably, neither D-2HG nor 3HP accumulation in these mutants explains embryonic lethality. Instead, ketone body metabolism genes are upregulated and supplementation of the ketone body 3-hydroxybutyrate (3HB) partially rescues embryonic lethality. Altogether, our findings suggest that propionate and ketone bodies are functionally connected to support C. elegans viability.
Competing Interest Statement
The authors have declared no competing interest.