Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

Christian Frezza, Liang Zheng, Ori Folger, Kartik N Rajagopalan, Elaine D MacKenzie, Livnat Jerby, Massimo Micaroni, Barbara Chaneton, Julie Adam, Ann Hedley, Gabriela Kalna, Ian P M Tomlinson, Patrick J Pollard, Dave G Watson, Ralph J Deberardinis, Tomer Shlomi, Eytan Ruppin, Eyal Gottlieb

Research output: Contribution to journalArticle

290 Citations (Scopus)

Abstract

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions2, 3, 4. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.
LanguageEnglish
Pages225–228
Number of pages4
JournalNature
Volume477
Issue number7363
DOIs
Publication statusPublished - 8 Sep 2011

Fingerprint

Fumarate Hydratase
Heme Oxygenase (Decyclizing)
Neoplasms
Citric Acid Cycle
Metabolic Networks and Pathways
Heme
Fumarates
Glutamine
Bilirubin
Computer Simulation
NAD
Oxygen
Kidney

Keywords

  • metabolic network
  • assay
  • protein
  • pathway
  • reconstruction
  • models
  • cells
  • in-vitro
  • renal-cancer
  • uterine fibroids

Cite this

Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., ... Gottlieb, E. (2011). Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature, 477(7363), 225–228. https://doi.org/10.1038/nature10363
Frezza, Christian ; Zheng, Liang ; Folger, Ori ; Rajagopalan, Kartik N ; MacKenzie, Elaine D ; Jerby, Livnat ; Micaroni, Massimo ; Chaneton, Barbara ; Adam, Julie ; Hedley, Ann ; Kalna, Gabriela ; Tomlinson, Ian P M ; Pollard, Patrick J ; Watson, Dave G ; Deberardinis, Ralph J ; Shlomi, Tomer ; Ruppin, Eytan ; Gottlieb, Eyal. / Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. In: Nature. 2011 ; Vol. 477, No. 7363. pp. 225–228.
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abstract = "Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions2, 3, 4. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.",
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Frezza, C, Zheng, L, Folger, O, Rajagopalan, KN, MacKenzie, ED, Jerby, L, Micaroni, M, Chaneton, B, Adam, J, Hedley, A, Kalna, G, Tomlinson, IPM, Pollard, PJ, Watson, DG, Deberardinis, RJ, Shlomi, T, Ruppin, E & Gottlieb, E 2011, 'Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase' Nature, vol. 477, no. 7363, pp. 225–228. https://doi.org/10.1038/nature10363

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. / Frezza, Christian; Zheng, Liang; Folger, Ori; Rajagopalan, Kartik N; MacKenzie, Elaine D; Jerby, Livnat; Micaroni, Massimo; Chaneton, Barbara; Adam, Julie; Hedley, Ann; Kalna, Gabriela; Tomlinson, Ian P M; Pollard, Patrick J; Watson, Dave G; Deberardinis, Ralph J; Shlomi, Tomer; Ruppin, Eytan; Gottlieb, Eyal.

In: Nature, Vol. 477, No. 7363, 08.09.2011, p. 225–228.

Research output: Contribution to journalArticle

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T1 - Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

AU - Frezza, Christian

AU - Zheng, Liang

AU - Folger, Ori

AU - Rajagopalan, Kartik N

AU - MacKenzie, Elaine D

AU - Jerby, Livnat

AU - Micaroni, Massimo

AU - Chaneton, Barbara

AU - Adam, Julie

AU - Hedley, Ann

AU - Kalna, Gabriela

AU - Tomlinson, Ian P M

AU - Pollard, Patrick J

AU - Watson, Dave G

AU - Deberardinis, Ralph J

AU - Shlomi, Tomer

AU - Ruppin, Eytan

AU - Gottlieb, Eyal

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N2 - Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions2, 3, 4. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.

AB - Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions2, 3, 4. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.

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Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. 2011 Sep 8;477(7363):225–228. https://doi.org/10.1038/nature10363