idh-1 neomorphic mutation confers sensitivity to vitamin B12 in Caenorhabditis elegans.
Life Sci Alliance
; 7(10)2024 Oct.
Article
em En
| MEDLINE
| ID: mdl-39009411
ABSTRACT
In humans, a neomorphic isocitrate dehydrogenase mutation (idh-1neo) causes increased levels of cellular D-2-hydroxyglutarate (D-2HG), a proposed oncometabolite. However, the physiological effects of increased D-2HG and whether additional metabolic changes occur in the presence of an idh-1neo mutation are not well understood. We created a Caenorhabditis elegans model to study the effects of the idh-1neo mutation in a whole animal. Comparing the phenotypes exhibited by the idh-1neo to ∆dhgd-1 (D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability in idh-1neo mutant animals that leads to increased embryonic lethality. Through a genetic screen, we found that impairment of the glycine cleavage system, which generates one-carbon donor units, exacerbates this phenotype. In addition, supplementation with alternate sources of one-carbon donors suppresses the lethal phenotype. Our results indicate that the idh-1neo mutation imposes a heightened dependency on the one-carbon pool and provides a further understanding of how this oncogenic mutation rewires cellular metabolism.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vitamina B 12
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Caenorhabditis elegans
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Proteínas de Caenorhabditis elegans
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Isocitrato Desidrogenase
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Mutação
Limite:
Animals
Idioma:
En
Revista:
Life Sci Alliance
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Life sci. alliance
/
Life science alliance
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos