IDH3α regulates one-carbon metabolism in glioblastoma

Jasmine L. May, Foteini Kouri, Lisa A. Hurley, Juan Liu, Serena Tommasini-Ghelfi, Yanrong Ji, Peng Gao, Andrea E. Calvert, Andrew Lee, Navdeep Chandel, Ramana V Davuluri, Craig Michael Horbinski, Jason W. Locasale, Alexander H Stegh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3α binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3α promotes methionine cycle activity, S-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3α-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.

Original languageEnglish (US)
Article numbereaat0456
JournalScience Advances
Issue number1
StatePublished - 2019

ASJC Scopus subject areas

  • General


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