idh-1 neomorphic mutation confers sensitivity to vitamin B12 via increased dependency on one-carbon metabolism in Caenorhabditis elegans

Ponomarova, O.; Starbard, A. N.; Belfi, A.; Anderson, A. V.; Sundaram, M. V.; Walhout, A. J.

doi:10.1101/2024.03.13.584865

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bioRxiv · 10.1101/2024.03.13.584865

idh-1 neomorphic mutation confers sensitivity to vitamin B12 via increased dependency on one-carbon metabolism in Caenorhabditis elegans

Ponomarova, O.·Starbard, A. N.·Belfi, A.·Anderson, A. V.·Sundaram, M. V.·Walhout, A. J.

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Abstract

The isocitrate dehydrogenase neomorphic mutation (idh-1neo) generates 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 C. elegans model to study the effects of the idh-1neo mutation in a whole animal. Comparing the phenotypes exhibited by the idh-1neo to{Delta} 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. Additionally, supplementation with an alternate source 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 how this oncogenic mutation rewires cellular metabolism.

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Ponomarova, O., Starbard, A. N., Belfi, A., Anderson, A. V., Sundaram, M. V., Walhout, A. J.. 2024-03-14. idh-1 neomorphic mutation confers sensitivity to vitamin B12 via increased dependency on one-carbon metabolism in Caenorhabditis elegans. https://doi.org/10.1101/2024.03.13.584865

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