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Free Radic Biol Med. 2018 May 20;120:102-113. doi: 10.1016/j.freeradbiomed.2018.03.022. Epub 2018 Mar 14.

Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts.

Author information

1
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
2
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
3
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, 14458 Nuthetal, Germany.
4
Department of Physiological Chemistry, Faculty of Chemisty, University of Vienna, 1090 Vienna, Austria.
5
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany.
6
NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, 14458 Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany.
7
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany; German Center for Cardiovascular Research (DZHK), 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, 14458 Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany. Electronic address: scientific.director@dife.de.

Abstract

Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2α pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging.

KEYWORDS:

Advanced glycation end products; Aging; Apoptosis; Collagen; ER stress; Methylglyoxal; Redox homeostasis

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