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. 2024 Jul 15;7(10):e202402924. doi: 10.26508/lsa.202402924

Figure 2. Vitamin B12 increases D-2HG levels and induces embryonic lethality in idh-1neo C. elegans.

Figure 2.

(A) GC-MS profiling of metabolic changes in idh-1neo C. elegans compared with WT animals. P-values are Benjamini–Hochberg adjusted. Alanine is a proteinogenic amino acid whereas β-alanine is a non-proteinogenic amino acid intermediate in pyrimidine, aspartate, and propionate metabolism. (B) Schematic of the propionate degradation shunt pathway. (C) GC-MS profiling of metabolic changes in idh-1neo C. elegans supplemented with vitamin B12 compared with non-supplemented idh-1neo animals. P-values are Benjamini–Hochberg adjusted. (D) 3HP abundance in idh-1neo mutants with and without supplemented vitamin B12. (E) Brood size and hatching rate of idh-1neo mutants. Bars represent mean and SD of three biological replicates. (F) Schematic of predicted IDH-1neo, HPHD-1, and DHGD-1 contributions to D-2HG accumulation. IDH-1neo is an introduced and HPHD-1 is an endogenous source of D-2HG. DHGD-1 recycles D-2HG by converting it to αKG. In idh-1neo animals, vitamin B12 causes an increase in D-2HG accumulation by repressing the expression of dhgd-1, which encodes the enzyme that converts D-2HG into αKG in the propionate shunt. Vitamin B12 also represses the expression of hphd-1, which is the enzyme that generates D-2HG in the propionate shunt. (G) 2HG abundance in idh-1neo mutants with and without supplemented vitamin B12. (H) 2HG abundance in idh-1neo mutants upon RNAi of dhgd-1 with and without supplemented vitamin B12. (I) Embryonic lethality of idh-1neo mutants upon RNAi of dhgd-1 with and without supplemented vitamin B12. ***P < 0.001. All panels show data for idh-1neo animals on a diet of E. coli OP50 or RNAi competent E. coli OP50 (xu363). (D, G, H) Boxplot midline in panels (D, G, H) represents median of independent biological replicates (dots).