Abstract
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.
Highlights
The enzyme aminoimidazole-4-carboxamide ribonucleoside (AICAR)-transformylase/inosine monophosphate (IMP) cyclohydrolase (ATIC) catalyzes the last two steps of purine de novo synthesis
We investigated whether the AICAR–AICAR-transformylase/IMP cyclohydrolase (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
This study identified C55F2.1 as the C. elegans homolog for the mammalian enzyme ATIC
Summary
The C. elegans homolog of atic-1, C55F2.1, was identified by in silico analysis. To verify its enzymatic function, a transgenic nematode (tgC55F2.1b) was created, and the activity of AICAR formyltransferase (AICARFT) was determined. The HG-mediated increase in the neuronal damage score to 1.29 Ϯ 0.12 (p Ͻ 0.001) was normalized by additional AICAR treatment to 0.59 Ϯ 0.13 (p ϭ 0.0007), whereas there was no effect under S conditions (Fig. 6F, first group) This effect was again lost when aak-2 was down-regulated (p ϭ 0.0758) (Fig. 6F, second group), whereas loss of the MG- and ROS-detoxifying enzymes glod-4 (p ϭ 0.0002) (Fig. 6F, third group) and sod-3 (p ϭ 0.0002) (Fig. 6F, fourth group) did not affect the AICAR action of structural damage under HG. Treatment with AICAR affected sod-3 and glod-4 independent of the accumulation of reactive metabolites and the expression of atic-1 mRNA (Fig. S5) This effect was more pronounced under HG than under S conditions but was most importantly lost in the absence of aak-2. It is important to note that hormesis-enabling ROS but, rather, HG-induced excessive the effects of rotenone and BHA were exclusively present in ROS production is responsible for the HG effects observed
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