A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia
More about Open Access at the CrickAuthors list
Julie Adam Ming Yang Christina Bauerschmidt Mitsuhiro Kitagawa Linda O'Flaherty Pratheesh Maheswaran Gizem Özkan Natasha Sahgal Dilair Baban Keiko Kato Kaori Saito Keiko Iino Kaori Igarashi Michael Stratford Christopher Pugh Daniel A Tennant Christian Ludwig Ben Davies Peter Ratcliffe Mona El-Bahrawy Houman Ashrafian Tomoyoshi Soga Patrick J PollardAbstract
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.
Full text links
Publisher website (DOI) 10.1016/j.celrep.2013.04.006
Europe PubMed Central 23643539
Pubmed 23643539
Keywords
Type of publication