Oxidants produced by Methylglyoxal-modified Collagen Trigger ER Stress and Apoptosis in Skin Fibroblasts

Publication date: Available online 14 March 2018
Source:Free Radical Biology and Medicine
Author(s): Kerstin Nowotny, José Pedro Castro, Martín Hugo, Sabine Braune, Daniela Weber, Marc Pignitter, Veronika Somoza, Julia Bornhorst, Tanja Schwerdtle, Tilman Grune
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.

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