Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Liang Zheng, Simone Cardaci, Livnat Jerby, Elaine D. Mackenzie, Marco Sciacovelli, T. Isaac Johnson, Edoardo Gaude, Ayala King, Joshua D.G. Leach, RuAngelie Edrada-Ebel, Ann Hedley, Nicholas A. Morrice, Galbriela Kalna, Karen Blyth, Eytan Ruppin, Christian Frezza, Eyal Gottlieb

Research output: Contribution to journalArticle

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Abstract

Mutations in the tricarboxylic acid (TCA) cycle enzyme ​fumarate hydratase (​FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of ​FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of ​fumarate caused by the inactivation of ​FH leads to oxidative stress that is mediated by the formation of ​succinicGSH, a covalent adduct between ​fumarate and ​glutathione. Chronic succination of ​GSH, caused by the loss of ​FH, or by exogenous ​fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of ​p21, a key mediator of senescence, in ​Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that ​fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.
LanguageEnglish
Article number6001
Number of pages12
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 23 Jan 2015

Fingerprint

Fumarates
glutathione
metabolism
Metabolism
Oxidation-Reduction
Glutathione
mice
cancer
analytical chemistry
cysts
Oxidative stress
Kidney Neoplasms
kidneys
mutations
deactivation
lesions
adducts
ablation
enzymes
Oxidative Stress

Keywords

  • ​fumarate hydratase
  • tricarboxilic acid cycle
  • renal cancer
  • succinic acid
  • cell biology

Cite this

Zheng, L., Cardaci, S., Jerby, L., Mackenzie, E. D., Sciacovelli, M., Johnson, T. I., ... Gottlieb, E. (2015). Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nature Communications, 6, [6001]. https://doi.org/10.1038/ncomms7001
Zheng, Liang ; Cardaci, Simone ; Jerby, Livnat ; Mackenzie, Elaine D. ; Sciacovelli, Marco ; Johnson, T. Isaac ; Gaude, Edoardo ; King, Ayala ; Leach, Joshua D.G. ; Edrada-Ebel, RuAngelie ; Hedley, Ann ; Morrice, Nicholas A. ; Kalna, Galbriela ; Blyth, Karen ; Ruppin, Eytan ; Frezza, Christian ; Gottlieb, Eyal. / Fumarate induces redox-dependent senescence by modifying glutathione metabolism. In: Nature Communications. 2015 ; Vol. 6.
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abstract = "Mutations in the tricarboxylic acid (TCA) cycle enzyme ​fumarate hydratase (​FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of ​FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of ​fumarate caused by the inactivation of ​FH leads to oxidative stress that is mediated by the formation of ​succinicGSH, a covalent adduct between ​fumarate and ​glutathione. Chronic succination of ​GSH, caused by the loss of ​FH, or by exogenous ​fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of ​p21, a key mediator of senescence, in ​Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that ​fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.",
keywords = "​fumarate hydratase , tricarboxilic acid cycle , renal cancer, succinic acid, cell biology",
author = "Liang Zheng and Simone Cardaci and Livnat Jerby and Mackenzie, {Elaine D.} and Marco Sciacovelli and Johnson, {T. Isaac} and Edoardo Gaude and Ayala King and Leach, {Joshua D.G.} and RuAngelie Edrada-Ebel and Ann Hedley and Morrice, {Nicholas A.} and Galbriela Kalna and Karen Blyth and Eytan Ruppin and Christian Frezza and Eyal Gottlieb",
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Zheng, L, Cardaci, S, Jerby, L, Mackenzie, ED, Sciacovelli, M, Johnson, TI, Gaude, E, King, A, Leach, JDG, Edrada-Ebel, R, Hedley, A, Morrice, NA, Kalna, G, Blyth, K, Ruppin, E, Frezza, C & Gottlieb, E 2015, 'Fumarate induces redox-dependent senescence by modifying glutathione metabolism' Nature Communications, vol. 6, 6001. https://doi.org/10.1038/ncomms7001

Fumarate induces redox-dependent senescence by modifying glutathione metabolism. / Zheng, Liang; Cardaci, Simone; Jerby, Livnat; Mackenzie, Elaine D.; Sciacovelli, Marco; Johnson, T. Isaac; Gaude, Edoardo; King, Ayala; Leach, Joshua D.G.; Edrada-Ebel, RuAngelie; Hedley, Ann; Morrice, Nicholas A.; Kalna, Galbriela; Blyth, Karen; Ruppin, Eytan; Frezza, Christian; Gottlieb, Eyal.

In: Nature Communications, Vol. 6, 6001, 23.01.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fumarate induces redox-dependent senescence by modifying glutathione metabolism

AU - Zheng, Liang

AU - Cardaci, Simone

AU - Jerby, Livnat

AU - Mackenzie, Elaine D.

AU - Sciacovelli, Marco

AU - Johnson, T. Isaac

AU - Gaude, Edoardo

AU - King, Ayala

AU - Leach, Joshua D.G.

AU - Edrada-Ebel, RuAngelie

AU - Hedley, Ann

AU - Morrice, Nicholas A.

AU - Kalna, Galbriela

AU - Blyth, Karen

AU - Ruppin, Eytan

AU - Frezza, Christian

AU - Gottlieb, Eyal

PY - 2015/1/23

Y1 - 2015/1/23

N2 - Mutations in the tricarboxylic acid (TCA) cycle enzyme ​fumarate hydratase (​FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of ​FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of ​fumarate caused by the inactivation of ​FH leads to oxidative stress that is mediated by the formation of ​succinicGSH, a covalent adduct between ​fumarate and ​glutathione. Chronic succination of ​GSH, caused by the loss of ​FH, or by exogenous ​fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of ​p21, a key mediator of senescence, in ​Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that ​fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

AB - Mutations in the tricarboxylic acid (TCA) cycle enzyme ​fumarate hydratase (​FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of ​FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of ​fumarate caused by the inactivation of ​FH leads to oxidative stress that is mediated by the formation of ​succinicGSH, a covalent adduct between ​fumarate and ​glutathione. Chronic succination of ​GSH, caused by the loss of ​FH, or by exogenous ​fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of ​p21, a key mediator of senescence, in ​Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that ​fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

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KW - renal cancer

KW - succinic acid

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DO - 10.1038/ncomms7001

M3 - Article

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JO - Nature Communications

T2 - Nature Communications

JF - Nature Communications

SN - 2041-1723

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ER -

Zheng L, Cardaci S, Jerby L, Mackenzie ED, Sciacovelli M, Johnson TI et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nature Communications. 2015 Jan 23;6. 6001. https://doi.org/10.1038/ncomms7001