Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells

E.D. MacKenzie, M.A. Selak, D.A. Tennant, L.J. Payne, S. Crosby, C.M. Frederiksen, D.G. Watson, E. Gottlieb

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1α stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFα prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, α-ketoglutarate. We designed and synthesized cell-permeating α-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular α-ketoglutarate. Introduction of α-ketoglutarate derivatives restores normal PHD activity and HIF1α levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.
LanguageEnglish
Pages3282-3289
Number of pages8
JournalMolecular and Cellular Biology
Volume27
Issue number9
DOIs
Publication statusPublished - May 2007

Fingerprint

Prolyl Hydroxylases
Succinate Dehydrogenase
Fumarate Hydratase
Citric Acid Cycle
Fumarates
Succinic Acid
Cell Hypoxia
Second Primary Neoplasms
Neoplasms
alpha-ketoglutaric acid

Keywords

  • succinate dehydrogenase (SDH)
  • fumarate hydratase (FH)
  • pseudohypoxia
  • TCA cycle dysfunction

Cite this

MacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., ... Gottlieb, E. (2007). Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Molecular and Cellular Biology, 27(9), 3282-3289. https://doi.org/10.1128/mcb.01927-06
MacKenzie, E.D. ; Selak, M.A. ; Tennant, D.A. ; Payne, L.J. ; Crosby, S. ; Frederiksen, C.M. ; Watson, D.G. ; Gottlieb, E. / Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 9. pp. 3282-3289.
@article{8f6b96be118044599d8959e98d78115b,
title = "Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells",
abstract = "Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1α stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFα prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, α-ketoglutarate. We designed and synthesized cell-permeating α-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular α-ketoglutarate. Introduction of α-ketoglutarate derivatives restores normal PHD activity and HIF1α levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.",
keywords = "succinate dehydrogenase (SDH), fumarate hydratase (FH) , pseudohypoxia, TCA cycle dysfunction",
author = "E.D. MacKenzie and M.A. Selak and D.A. Tennant and L.J. Payne and S. Crosby and C.M. Frederiksen and D.G. Watson and E. Gottlieb",
year = "2007",
month = "5",
doi = "10.1128/mcb.01927-06",
language = "English",
volume = "27",
pages = "3282--3289",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
number = "9",

}

MacKenzie, ED, Selak, MA, Tennant, DA, Payne, LJ, Crosby, S, Frederiksen, CM, Watson, DG & Gottlieb, E 2007, 'Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells' Molecular and Cellular Biology, vol. 27, no. 9, pp. 3282-3289. https://doi.org/10.1128/mcb.01927-06

Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. / MacKenzie, E.D.; Selak, M.A.; Tennant, D.A.; Payne, L.J.; Crosby, S.; Frederiksen, C.M.; Watson, D.G.; Gottlieb, E.

In: Molecular and Cellular Biology, Vol. 27, No. 9, 05.2007, p. 3282-3289.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells

AU - MacKenzie, E.D.

AU - Selak, M.A.

AU - Tennant, D.A.

AU - Payne, L.J.

AU - Crosby, S.

AU - Frederiksen, C.M.

AU - Watson, D.G.

AU - Gottlieb, E.

PY - 2007/5

Y1 - 2007/5

N2 - Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1α stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFα prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, α-ketoglutarate. We designed and synthesized cell-permeating α-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular α-ketoglutarate. Introduction of α-ketoglutarate derivatives restores normal PHD activity and HIF1α levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.

AB - Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1α stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFα prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, α-ketoglutarate. We designed and synthesized cell-permeating α-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular α-ketoglutarate. Introduction of α-ketoglutarate derivatives restores normal PHD activity and HIF1α levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.

KW - succinate dehydrogenase (SDH)

KW - fumarate hydratase (FH)

KW - pseudohypoxia

KW - TCA cycle dysfunction

U2 - 10.1128/mcb.01927-06

DO - 10.1128/mcb.01927-06

M3 - Article

VL - 27

SP - 3282

EP - 3289

JO - Molecular and Cellular Biology

T2 - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 9

ER -