Biomedical Engineering Reference
In-Depth Information
Chapter 1
Protein Misfolding and Cellular Stress: An Overview
Niels Gregersen and Peter Bross
Abstract
Cell survival and death are complex matters. Too much survival may lead to cancer and too much cell
death may result in tissue degeneration. In this chapter, we will first of all focus on the cellular survival
mechanisms that promote correct folding and maintenance of protein function. These mechanisms
include protein quality control (PQC) systems comprising molecular chaperones and intracellular pro-
teases in the cytosol, endoplasmatic reticulum (ER) and in the mitochondria. In addition to the PQC
systems, mechanisms elicited by misfolded proteins, known as unfolded protein responses (UPRs),
including induction/activation of antioxidant systems are also present in the three compartments of the
cell. Second, we will discuss the mechanisms by which misfolded proteins lead to the generation of oxida-
tive stress in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These spe-
cies are produced mainly from superoxide (O
2
-
) generated in the mitochondrial respiratory chain and
from nitrogen oxide (NO) produced by the mitochondrial nitrogen oxide synthetase (mtNOS). Third,
the effects of oxidative stress will be discussed, both with respect to mitochondrial dynamics, i.e., fission
and fusion, and the related elimination of dysfunctional mitochondria by cellular cleaning systems, i.e.,
mitophagy or mitoptosis, and related to the generation and cellular effects of oxidatively modified pro-
teins, which closes a vicious cycle of protein misfolding and oxidative stress.
Key words:
Protein misfolding, Unfolded protein response, Heat shock response, Oxidative stress,
Reactive oxygen species, Reactive nitrogen species, Protein quality control system, Antioxidative
defense, Reactive carbonyl compounds
1. Introduction
All living cells contain molecular systems that are vital for proper
function and survival. Among these, organelle specific networks of
protein quality control (PQC) systems, comprising molecular
chaperones and intracellular proteases, as well as antioxidant systems,
maintain appropriate protein folding, structure, and function.
Although an important function of the chaperone components
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