Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Aug 17;477(7363):225-8.
doi: 10.1038/nature10363.

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

Christian Frezza  1 , 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
Affiliations

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

Christian Frezza et al. Nature. .

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). 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 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.

PubMed Disclaimer

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1777-82 - PubMed
    1. Cancer Cell. 2007 Apr;11(4):311-9 - PubMed
    1. Am J Physiol Gastrointest Liver Physiol. 2004 Dec;287(6):G1150-7 - PubMed
    1. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50 - PubMed
    1. Clin Chem. 1999 Dec;45(12):2060-72 - PubMed

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources