Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma.
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 alpha-ketoglutarate (alphaKG)-dependent enzyme Jlp1, involved in sulfur metabolism, and alphaKG-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 alphaKG-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.
Smith
Emily H
EH
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA .
Janknecht
Ralf
R
Maher
L James
LJ
D002478:Cells, Cultured; D002952:Citric Acid Cycle; D049308:Dioxygenases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D007656:Ketoglutaric Acids / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D030781:Organisms, Genetically Modified; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D010235:Paraganglioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000378:metabolism / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007656:Ketoglutaric Acids; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D019802:Succinic Acid; D006899:Mixed Function Oxygenases; D049308:Dioxygenases; C121605:JLP1 protein, S cerevisiae; C521733:Jhd1 protein, S cerevisiae; D056484:Jumonji Domain-Containing Histone Demethylases; D013385:Succinate Dehydrogenase; D010089:Oxidoreductases, N-Demethylating