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High-glucose toxicity is mediated by AICAR-transformylase/ IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans.
J. Biol. Chem. 293, 4845-4859 (2018)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Aicar ; Amp-activated Kinase (ampk) ; Atic ; Caenorhabditis Elegans (c. Elegans) ; Dna Damage ; Diabetes ; Reactive Oxygen Species (ros); Increasing Oxidative Stress; Type-2 Diabetes-mellitus; Double-strand Breaks; Life-span; Dna-damage; C-elegans; 5-aminoimidazole-4-carboxamide Ribonucleoside; Reactive Metabolites; Gene-transfer; Insulin
ISSN (print) / ISBN
0021-9258
e-ISSN
1083-351X
Quellenangaben
Volume: 293,
Issue: 13,
Pages: 4845-4859
Publisher
American Society for Biochemistry and Molecular Biology
Publishing Place
Bethesda
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Cancer (IDC)