The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de-novo synthesis. It metabolizes AICAR, which is an AMP analogue, leading to activation of AMPK. It was 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 damages and shortening of lifespan. HG up-regulated the expression and activity of Caenorhabditis elegans homologue of ATIC, C55F2.1 (
atic-1), as well as increased the levels of reactive oxygen species (ROS) and methylglyoxalderived advanced glycation endproducts (MG-AGEs). Overexpression of
atic-1 decreased lifespan and head motility and increased neuronal damage under both standard (S) and high glucose (HG) conditions. Inhibition of
atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, ROS and MG-AGE 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 upon AMPK and an 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.