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Riedinger, C.* ; Mendler, M.* ; Schlotterer, A.* ; Fleming, T.* ; Okun, J.G.* ; Hammes, H.P.* ; Herzig, S. ; Nawroth, P.P.*

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)
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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 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Publishing Place Bethesda
Reviewing status Peer reviewed