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

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

Author information

1
From the Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
2
the Department of Pediatrics, Dietmar Hopp Metabolism Centre, 69120 Heidelberg, Germany.
3
the V. Medical Hospital, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
4
the Institute for Diabetes and Cancer, Helmholtz Center Munich, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
5
the Joint Heidelberg Institute for Diabetes and Cancer Translational Diabetes Program, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany, and.
6
the German Center for Diabetes Research, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
7
From the Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany, peter.nawroth@med.uni-heidelberg.de.

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.

KEYWORDS:

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

PMID:
29414769
PMCID:
PMC5880143
DOI:
10.1074/jbc.M117.805879
[Indexed for MEDLINE]
Free PMC Article

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