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 journalArticle

2 Citations (Scopus)

Abstract

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
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Glioblastoma
Glycine Hydroxymethyltransferase
Carbon
Methionine
Activity Cycles
Isocitrate Dehydrogenase
Citric Acid Cycle
Oxidative Phosphorylation
DNA Methylation
DNA Replication
Epigenomics
Glioma
Energy Metabolism
Up-Regulation
Nucleotides
Gene Expression
Mutation
Brain
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

May, J. L., Kouri, F., Hurley, L. A., Liu, J., Tommasini-Ghelfi, S., Ji, Y., ... Stegh, A. H. (2019). IDH3α regulates one-carbon metabolism in glioblastoma. Science Advances, 5(1), [eaat0456]. https://doi.org/10.1126/sciadv.aat0456
May, Jasmine L. ; Kouri, Foteini ; Hurley, Lisa A. ; Liu, Juan ; Tommasini-Ghelfi, Serena ; Ji, Yanrong ; Gao, Peng ; Calvert, Andrea E. ; Lee, Andrew ; Chandel, Navdeep ; Davuluri, Ramana V ; Horbinski, Craig Michael ; Locasale, Jason W. ; Stegh, Alexander H. / IDH3α regulates one-carbon metabolism in glioblastoma. In: Science Advances. 2019 ; Vol. 5, No. 1.
@article{5597190aa6ca489a935e6f899f21aff3,
title = "IDH3α regulates one-carbon metabolism in glioblastoma",
abstract = "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.",
author = "May, {Jasmine L.} and Foteini Kouri and Hurley, {Lisa A.} and Juan Liu and Serena Tommasini-Ghelfi and Yanrong Ji and Peng Gao and Calvert, {Andrea E.} and Andrew Lee and Navdeep Chandel and Davuluri, {Ramana V} and Horbinski, {Craig Michael} and Locasale, {Jason W.} and Stegh, {Alexander H}",
year = "2019",
month = "1",
day = "1",
doi = "10.1126/sciadv.aat0456",
language = "English (US)",
volume = "5",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "1",

}

May, JL, Kouri, F, Hurley, LA, Liu, J, Tommasini-Ghelfi, S, Ji, Y, Gao, P, Calvert, AE, Lee, A, Chandel, N, Davuluri, RV, Horbinski, CM, Locasale, JW & Stegh, AH 2019, 'IDH3α regulates one-carbon metabolism in glioblastoma', Science Advances, vol. 5, no. 1, eaat0456. https://doi.org/10.1126/sciadv.aat0456

IDH3α regulates one-carbon metabolism in glioblastoma. / May, Jasmine L.; Kouri, Foteini; Hurley, Lisa A.; Liu, Juan; Tommasini-Ghelfi, Serena; Ji, Yanrong; Gao, Peng; Calvert, Andrea E.; Lee, Andrew; Chandel, Navdeep; Davuluri, Ramana V; Horbinski, Craig Michael; Locasale, Jason W.; Stegh, Alexander H.

In: Science Advances, Vol. 5, No. 1, eaat0456, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IDH3α regulates one-carbon metabolism in glioblastoma

AU - May, Jasmine L.

AU - Kouri, Foteini

AU - Hurley, Lisa A.

AU - Liu, Juan

AU - Tommasini-Ghelfi, Serena

AU - Ji, Yanrong

AU - Gao, Peng

AU - Calvert, Andrea E.

AU - Lee, Andrew

AU - Chandel, Navdeep

AU - Davuluri, Ramana V

AU - Horbinski, Craig Michael

AU - Locasale, Jason W.

AU - Stegh, Alexander H

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85059499375&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059499375&partnerID=8YFLogxK

U2 - 10.1126/sciadv.aat0456

DO - 10.1126/sciadv.aat0456

M3 - Article

VL - 5

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 1

M1 - eaat0456

ER -

May JL, Kouri F, Hurley LA, Liu J, Tommasini-Ghelfi S, Ji Y et al. IDH3α regulates one-carbon metabolism in glioblastoma. Science Advances. 2019 Jan 1;5(1). eaat0456. https://doi.org/10.1126/sciadv.aat0456