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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Collagen / drug effects
  • Collagen / metabolism
  • Endoplasmic Reticulum Stress / physiology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Glycation End Products, Advanced / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Oxidants / metabolism
  • Pyruvaldehyde / metabolism*
  • Pyruvaldehyde / toxicity
  • Skin

Substances

  • Glycation End Products, Advanced
  • Oxidants
  • Pyruvaldehyde
  • Collagen