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- Title
A D-2-hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development.
- 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.
- Abstract
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. In humans, mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) cause delayed development, seizures and ataxia. This study shows that in the nematode Caenorhabditis elegans, D2HGDH sustains ketone body production to support embryonic viability; its loss results in mitochondrial defects and embryonic lethality,
- Subjects
KETONES; VITAMIN B12; CAENORHABDITIS elegans; NEUROCYSTICERCOSIS; DIETARY supplements; METABOLISM; 3-Hydroxybutyric acid; ATAXIA
- Publication
PLoS Biology, 2023, Vol 21, Issue 4, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002057