Succinate inhibition of α-ketoglutarate-dependent enzymes in a yeast model of paraganglioma

Emily H. Smith, Ralf Janknecht, James L. Maher

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a tumor suppressor. Heterozygosity for defective SDH subunit genes predisposes to familial paraganglioma (PGL) or pheochromocytoma (PHEO). Models invoking reactive oxygen species (ROS) or succinate accumulation have been proposed to explain the link between TCA cycle dysfunction and oncogenesis. Here we study the biochemical consequences of a common familial PGL-linked mutation, loss of the SDHB subunit, in a yeast model. This strain has increased ROS production but no evidence of mutagenic DNA damage. Because the strain lacks SDH activity, succinate accumulates dramatically and inhibits α-ketoglutarate (αKG)-dependent enzyme Jlp1, involved in sulfur metabolism, and αKG-dependent histone demethylase Jhd1. We show that mammalian JmjC-domain histone demethylases are also vulnerable to succinate inhibition in vitro and in cultured cells. Our results suggest that any αKG-dependent enzyme is a potential target of accumulated succinate in oncogenesis. The possible role that inhibition of these enzymes by succinate may have in oncogenesis is discussed.

Original languageEnglish (US)
Pages (from-to)3136-3148
Number of pages13
JournalHuman molecular genetics
Volume16
Issue number24
DOIs
StatePublished - Dec 15 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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