A D-2-hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development

• Published in: PLoS biology Vol. 21; no. 4; p. e3002057
• Main Authors: Ponomarova, Olga, Zhang, Hefei, Li, Xuhang, Nanda, Shivani, Leland, Thomas B, Fox, Bennett W, Starbard, Alyxandra N, Giese, Gabrielle E, Schroeder, Frank C, Yilmaz, L Safak, Walhout, Albertha J M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12-04-2023; Public Library of Science (PLoS)
• Subjects: 2-Hydroxyglutarate dehydrogenase; Amino acids; Analysis; Animals; Ataxia; Biology and Life Sciences; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Chromatography; Cyanocobalamin; Dehydrogenase; Dehydrogenases; Enzymes; Fatty acids; Gene mutations; Genes; Genetic aspects; Humans; Identification and classification; Ketones; Lethality; Mass spectrometry; Medicine and Health Sciences; Metabolism; Metabolites; Mitochondria; Mutation; Nematodes; Oxidoreductases; Physical Sciences; Physiology; Propionates - metabolism; Propionic acid; Research and Analysis Methods; RNA-mediated interference; Scientific imaging; Seizures; Short Reports; Vitamin B 12; Vitamin B12; United States
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002057

In humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Loss of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the up-regulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG or by supplementing either vitamin B12 or the ketone bodies 3-hydroxybutyrate (3HB) and acetoacetate (AA). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low and in which a loss of dhgd-1 causes lethality by limiting ketone body production.