D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

An Ping Lin; Saman Abbas; Sang Woo Kim; Manoela Ortega; Hakim Bouamar; Yissela Escobedo; Prakash Varadarajan; Yuejuan Qin; Jessica Sudderth; Eduard Schulz; Alexander Deutsch; Sumitra Mohan; Peter Ulz; Peter Neumeister; Dinesh Rakheja; Xiaoli Gao; Andrew Hinck; Susan T. Weintraub; Ralph J. DeBerardinis; Heinz Sill; Patricia L.M. Dahia; Ricardo C.T. Aguiar

doi:10.1038/ncomms8768

D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

An Ping Lin, Saman Abbas, Sang Woo Kim, Manoela Ortega, Hakim Bouamar, Yissela Escobedo, Prakash Varadarajan, Yuejuan Qin, Jessica Sudderth, Eduard Schulz, Alexander Deutsch, Sumitra Mohan, Peter Ulz, Peter Neumeister, Dinesh Rakheja, Xiaoli Gao, Andrew Hinck, Susan T. Weintraub, Ralph J. DeBerardinis, Heinz SillPatricia L.M. Dahia, Ricardo C.T. Aguiar

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Abstract

Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.

Original language	English (US)
Article number	7768
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8768
State	Published - Jul 16 2015

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Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Lin, A. P., Abbas, S., Kim, S. W., Ortega, M., Bouamar, H., Escobedo, Y., Varadarajan, P., Qin, Y., Sudderth, J., Schulz, E., Deutsch, A., Mohan, S., Ulz, P., Neumeister, P., Rakheja, D., Gao, X., Hinck, A., Weintraub, S. T., DeBerardinis, R. J., ... Aguiar, R. C. T. (2015). D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nature communications, 6, [7768]. https://doi.org/10.1038/ncomms8768

Lin, AP, Abbas, S, Kim, SW, Ortega, M, Bouamar, H, Escobedo, Y, Varadarajan, P, Qin, Y, Sudderth, J, Schulz, E, Deutsch, A, Mohan, S, Ulz, P, Neumeister, P, Rakheja, D, Gao, X, Hinck, A, Weintraub, ST, DeBerardinis, RJ, Sill, H, Dahia, PLM & Aguiar, RCT 2015, 'D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2', Nature communications, vol. 6, 7768. https://doi.org/10.1038/ncomms8768

@article{0ed2f43fd6324c888b19e924f5fc9173,

title = "D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2",

abstract = "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.",

author = "Lin, {An Ping} and Saman Abbas and Kim, {Sang Woo} and Manoela Ortega and Hakim Bouamar and Yissela Escobedo and Prakash Varadarajan and Yuejuan Qin and Jessica Sudderth and Eduard Schulz and Alexander Deutsch and Sumitra Mohan and Peter Ulz and Peter Neumeister and Dinesh Rakheja and Xiaoli Gao and Andrew Hinck and Weintraub, {Susan T.} and DeBerardinis, {Ralph J.} and Heinz Sill and Dahia, {Patricia L.M.} and Aguiar, {Ricardo C.T.}",

note = "Funding Information: We thank Marsha Kinney and the Pathology Core Laboratory at the University of Texas HSC San Antonio for procurement of the primary DLBCL samples; C. Beham-Schmid for providing bone marrow specimens; K. Lind and S. Hofer for VNTR analyses. This work was supported by an NIH grant R01-CA138747 (to R.C.T.A.), a CPRIT award RP140452 (to R.C.T.A.), Young Investigator Awards from the Voelcker Fund (to P.L.M.D. and R.C.T.A.), Leuk{\"a}miehilfe Steiermark (to H.S.), and a Cancer Center support grant P30 CA054174. Mass spectrometry analyses were conducted in the metabo-lomics component of the UTHSCSA Mass Spectrometry Laboratory, supported by UTHSCSA and by an award from the National Institutes of Health, 1S10RR031586-01 (S.T.W.). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jul,

day = "16",

doi = "10.1038/ncomms8768",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

AU - Lin, An Ping

AU - Abbas, Saman

AU - Kim, Sang Woo

AU - Ortega, Manoela

AU - Bouamar, Hakim

AU - Escobedo, Yissela

AU - Varadarajan, Prakash

AU - Qin, Yuejuan

AU - Sudderth, Jessica

AU - Schulz, Eduard

AU - Deutsch, Alexander

AU - Mohan, Sumitra

AU - Ulz, Peter

AU - Neumeister, Peter

AU - Rakheja, Dinesh

AU - Gao, Xiaoli

AU - Hinck, Andrew

AU - Weintraub, Susan T.

AU - DeBerardinis, Ralph J.

AU - Sill, Heinz

AU - Dahia, Patricia L.M.

AU - Aguiar, Ricardo C.T.

N1 - Funding Information: We thank Marsha Kinney and the Pathology Core Laboratory at the University of Texas HSC San Antonio for procurement of the primary DLBCL samples; C. Beham-Schmid for providing bone marrow specimens; K. Lind and S. Hofer for VNTR analyses. This work was supported by an NIH grant R01-CA138747 (to R.C.T.A.), a CPRIT award RP140452 (to R.C.T.A.), Young Investigator Awards from the Voelcker Fund (to P.L.M.D. and R.C.T.A.), Leukämiehilfe Steiermark (to H.S.), and a Cancer Center support grant P30 CA054174. Mass spectrometry analyses were conducted in the metabo-lomics component of the UTHSCSA Mass Spectrometry Laboratory, supported by UTHSCSA and by an award from the National Institutes of Health, 1S10RR031586-01 (S.T.W.). Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/7/16

Y1 - 2015/7/16

N2 - Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.

AB - Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.

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JO - Nature Communications

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ER -

D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

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