D-2-Hydroxyglutarate dehydrogenase connects the propionate shunt to ketone body metabolism in Caenorhabditis elegans

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-2HG[1][1]. D-2HG inhibits multiple metabolic enzymes[2][2]-[4][3] and promotes tumorigenesis[5][4],[6][5], 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. [1]: #ref-1 [2]: #ref-2 [3]: #ref-4 [4]: #ref-5 [5]: #ref-6