A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia

Cell Rep. 2013 May 30;3(5):1440-8. doi: 10.1016/j.celrep.2013.04.006. Epub 2013 May 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / metabolism
  • Argininosuccinic Acid / metabolism
  • Cell Line
  • Citric Acid Cycle
  • Fumarate Hydratase / deficiency
  • Fumarate Hydratase / genetics
  • Fumarate Hydratase / metabolism*
  • Fumarates / metabolism
  • Kidney / enzymology
  • Kidney Neoplasms / enzymology*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Metabolome
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mutation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Urea / metabolism

Substances

  • Fumarates
  • Protein Isoforms
  • Argininosuccinic Acid
  • Urea
  • Arginine
  • Fumarate Hydratase