Pathophysiological importance of aggregated damaged proteins

Free Radic Biol Med. 2014 Jun;71:70-89. doi: 10.1016/j.freeradbiomed.2014.02.028. Epub 2014 Mar 12.

Abstract

Reactive oxygen species (ROS) are formed continuously in the organism even under physiological conditions. If the level of ROS in cells exceeds the cellular defense capacity, components such as RNA/DNA, lipids, and proteins are damaged and modified, thus affecting the functionality of organelles as well. Proteins are especially prominent targets of various modifications such as oxidation, glycation, or conjugation with products of lipid peroxidation, leading to the alteration of their biological function, nonspecific interactions, and the production of high-molecular-weight protein aggregates. To ensure the maintenance of cellular functions, two proteolytic systems are responsible for the removal of oxidized and modified proteins, especially the proteasome and organelles, mainly the autophagy-lysosomal systems. Furthermore, increased protein oxidation and oxidation-dependent impairment of proteolytic systems lead to an accumulation of oxidized proteins and finally to the formation of nondegradable protein aggregates. Accordingly, the cellular homeostasis cannot be maintained and the cellular metabolism is negatively affected. Here we address the current knowledge of protein aggregation during oxidative stress, aging, and disease.

Keywords: Autophagy; Free radicals; Lipofuscin; Proteasome; Protein aggregates; Protein oxidation.

Publication types

  • Review

MeSH terms

  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Autophagy
  • Homeostasis
  • Humans
  • Lysosomes / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Aggregates
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / physiopathology
  • Protein Processing, Post-Translational*
  • Proteins / chemistry
  • Proteins / metabolism*
  • Proteolysis
  • Reactive Oxygen Species / metabolism

Substances

  • Protein Aggregates
  • Proteins
  • Reactive Oxygen Species
  • Proteasome Endopeptidase Complex