D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function

Masato Sasaki; Christiane B. Knobbe; Momoe Itsumi; Andrew J. Elia; Isaac S. Harris; Iok In Christine Chio; Rob A. Cairns; Susan Mccracken; Andrew Wakeham; Jillian Haight; Annick You Ten; Bryan Snow; Takeshi Ueda; Satoshi Inoue; Kazuo Yamamoto; Myunggon Ko; Anjana Rao; Katharine E. Yen; Shinsan M. Su; Tak Wah Mak

doi:10.1101/gad.198200.112

D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function

Masato Sasaki, Christiane B. Knobbe, Momoe Itsumi, Andrew J. Elia, Isaac S. Harris, Iok In Christine Chio, Rob A. Cairns, Susan Mccracken, Andrew Wakeham, Jillian Haight, Annick You Ten, Bryan Snow, Takeshi Ueda, Satoshi Inoue, Kazuo Yamamoto, Myunggon Ko, Anjana Rao, Katharine E. Yen, Shinsan M. Su, Tak Wah Mak

Research output: Contribution to journal › Article › peer-review

Abstract

Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP⁺/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.

Original language	English
Pages (from-to)	2038-2049
Number of pages	12
Journal	Genes and Development
Volume	26
Issue number	18
DOIs	https://doi.org/10.1101/gad.198200.112
Publication status	Published - 2012 Sept 15
Externally published	Yes

Keywords

Angiogenesis
Basement membrane
Brain hemorrhage
Collagen biosynthesis
Metabolism
Oxidative stress

ASJC Scopus subject areas

Genetics
Developmental Biology

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10.1101/gad.198200.112

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Sasaki, M., Knobbe, C. B., Itsumi, M., Elia, A. J., Harris, I. S., Chio, I. I. C., Cairns, R. A., Mccracken, S., Wakeham, A., Haight, J., Ten, A. Y., Snow, B., Ueda, T., Inoue, S., Yamamoto, K., Ko, M., Rao, A., Yen, K. E., Su, S. M., & Mak, T. W. (2012). D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function. Genes and Development, 26(18), 2038-2049. https://doi.org/10.1101/gad.198200.112

Sasaki, M, Knobbe, CB, Itsumi, M, Elia, AJ, Harris, IS, Chio, IIC, Cairns, RA, Mccracken, S, Wakeham, A, Haight, J, Ten, AY, Snow, B, Ueda, T, Inoue, S, Yamamoto, K, Ko, M, Rao, A, Yen, KE, Su, SM & Mak, TW 2012, 'D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function', Genes and Development, vol. 26, no. 18, pp. 2038-2049. https://doi.org/10.1101/gad.198200.112

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title = "D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function",

abstract = "Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP+/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.",

keywords = "Angiogenesis, Basement membrane, Brain hemorrhage, Collagen biosynthesis, Metabolism, Oxidative stress",

author = "Masato Sasaki and Knobbe, {Christiane B.} and Momoe Itsumi and Elia, {Andrew J.} and Harris, {Isaac S.} and Chio, {Iok In Christine} and Cairns, {Rob A.} and Susan Mccracken and Andrew Wakeham and Jillian Haight and Ten, {Annick You} and Bryan Snow and Takeshi Ueda and Satoshi Inoue and Kazuo Yamamoto and Myunggon Ko and Anjana Rao and Yen, {Katharine E.} and Su, {Shinsan M.} and Mak, {Tak Wah}",

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doi = "10.1101/gad.198200.112",

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AU - Sasaki, Masato

AU - Knobbe, Christiane B.

AU - Itsumi, Momoe

AU - Elia, Andrew J.

AU - Harris, Isaac S.

AU - Chio, Iok In Christine

AU - Cairns, Rob A.

AU - Mccracken, Susan

AU - Wakeham, Andrew

AU - Haight, Jillian

AU - Ten, Annick You

AU - Snow, Bryan

AU - Ueda, Takeshi

AU - Inoue, Satoshi

AU - Yamamoto, Kazuo

AU - Ko, Myunggon

AU - Rao, Anjana

AU - Yen, Katharine E.

AU - Su, Shinsan M.

AU - Mak, Tak Wah

PY - 2012/9/15

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N2 - Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP+/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.

AB - Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP+/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.

KW - Angiogenesis

KW - Basement membrane

KW - Brain hemorrhage

KW - Collagen biosynthesis

KW - Metabolism

KW - Oxidative stress

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JO - Genes and Development

JF - Genes and Development

IS - 18

ER -

D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function

Abstract

Keywords

ASJC Scopus subject areas

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