RT Journal Article
SR Electronic
T1 <em>idh-1</em> neomorphic mutation confers sensitivity to vitamin B12 in <em>Caenorhabditis elegans</em>
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402924
DO 10.26508/lsa.202402924
VO 7
IS 10
A1 Ponomarova, Olga
A1 Starbard, Alyxandra N
A1 Belfi, Alexandra
A1 Anderson, Amanda V
A1 Sundaram, Meera V
A1 Walhout, Albertha JM
YR 2024
UL http://www.life-science-alliance.org/content/7/10/e202402924.abstract
AB 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.