A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2013 May 7

PMID 23643539

Citations 47

Authors

Julie Adam

Ming Yang

Christina Bauerschmidt

Mitsuhiro Kitagawa

Linda OFlaherty

Pratheesh Maheswaran

Gizem Ozkan

Natasha Sahgal

Dilair Baban

Keiko Kato

Kaori Saito

Keiko Iino

Kaori Igarashi

Michael Stratford

Christopher Pugh

Daniel A Tennant

Christian Ludwig

Benjamin Davies

Peter J Ratcliffe

Mona El-Bahrawy

Houman Ashrafian

Tomoyoshi Soga

Patrick J Pollard

Affiliations

Soon will be listed here.

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.

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