title: A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia.
abstract: The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
authors: Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
authors: Julie
authors: J
authors: Adam
authors: Ming
authors: M
authors: Yang
authors: Christina
authors: C
authors: Bauerschmidt
authors: Mitsuhiro
authors: M
authors: Kitagawa
authors: Linda
authors: L
authors: O'Flaherty
authors: Pratheesh
authors: P
authors: Maheswaran
authors: Gizem
authors: G
authors: Özkan
authors: Natasha
authors: N
authors: Sahgal
authors: Dilair
authors: D
authors: Baban
authors: Keiko
authors: K
authors: Kato
authors: Kaori
authors: K
authors: Saito
authors: Keiko
authors: K
authors: Iino
authors: Kaori
authors: K
authors: Igarashi
authors: Michael
authors: M
authors: Stratford
authors: Christopher
authors: C
authors: Pugh
authors: Daniel A
authors: DA
authors: Tennant
authors: Christian
authors: C
authors: Ludwig
authors: Benjamin
authors: B
authors: Davies
authors: Peter J
authors: PJ
authors: Ratcliffe
authors: Mona
authors: M
authors: El-Bahrawy
authors: Houman
authors: H
authors: Ashrafian
authors: Tomoyoshi
authors: T
authors: Soga
authors: Patrick J
authors: PJ
authors: Pollard
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D001125:Argininosuccinic Acid / Q000378:metabolism; D002460:Cell Line; D002952:Citric Acid Cycle; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005650:Fumarates / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000378:metabolism
chemical_list: D005650:Fumarates; D020033:Protein Isoforms; D001125:Argininosuccinic Acid; D014508:Urea; D001120:Arginine; D005649:Fumarate Hydratase
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