High-glucose toxicity is mediated by AICAR-transformylase/IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans

J Biol Chem. 2018 Mar 30;293(13):4845-4859. doi: 10.1074/jbc.M117.805879. Epub 2018 Feb 2.


The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de novo synthesis. It metabolizes 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is an AMP analogue, leading to activation of AMP-activated kinase (AMPK). We investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG)-mediated DNA damage response and AICAR-mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damage and shortening of the lifespan. HG up-regulated the expression and activity of the Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), and increased the levels of reactive oxygen species and methylglyoxal-derived advanced glycation end products. Overexpression of atic-1 decreased the lifespan and head motility and increased neuronal damage under both standard and HG conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, reactive oxygen species, and methylglyoxal-derived advanced glycation end product accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent on AMPK and accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction.

Keywords: AICAR; AMP-activated kinase (AMPK); ATIC; Caenorhabditis elegans (C. elegans); DNA damage; diabetes; reactive oxygen species (ROS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Glucose / metabolism*
  • Hydroxymethyl and Formyl Transferases / genetics
  • Hydroxymethyl and Formyl Transferases / metabolism*
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Neurons / metabolism
  • Nucleotide Deaminases / genetics
  • Nucleotide Deaminases / metabolism*
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism


  • Caenorhabditis elegans Proteins
  • Multienzyme Complexes
  • Reactive Oxygen Species
  • inosine monophosphate synthase
  • Superoxide Dismutase
  • Hydroxymethyl and Formyl Transferases
  • AMP-Activated Protein Kinases
  • Nucleotide Deaminases
  • Glucose