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Review
. 2014 Aug;42(4):917-21.
doi: 10.1042/BST20140108.

About the Dangers, Costs and Benefits of Living an Aerobic Lifestyle

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Free PMC article
Review

About the Dangers, Costs and Benefits of Living an Aerobic Lifestyle

Daniela Knoefler et al. Biochem Soc Trans. .
Free PMC article

Abstract

The era in which ROS (reactive oxygen species) were simply the 'bad boys of biology' is clearly over. High levels of ROS are still rightfully considered to be toxic to many cellular processes and, as such, contribute to disease conditions and cell death. However, the high toxicity of ROS is also extremely beneficial, particularly as it is used to kill invading micro-organisms during mammalian host defence. Moreover, a transient, often more localized, increase in ROS levels appears to play a major role in signal transduction processes and positively affects cell growth, development and differentiation. At the heart of all these processes are redox-regulated proteins, which use oxidation-sensitive cysteine residues to control their function and by extension the function of the pathways that they are part of. Our work has contributed to changing the view about ROS through: (i) our characterization of Hsp33 (heat-shock protein 33), one of the first redox-regulated proteins identified, whose function is specifically activated by ROS, (ii) the development of quantitative tools that reveal extensive redox-sensitive processes in bacteria and eukaryotes, and (iii) the discovery of a link between early exposure to oxidants and aging. Our future research programme aims to generate an integrated and system-wide view of the beneficial and deleterious effects of ROS with the central goal to develop more effective antioxidant strategies and more powerful antimicrobial agents.

Figures

Figure 1
Figure 1. Keeping the balance between oxidants and antioxidants
ROS, including superoxide, peroxide and hydroxyl radicals, are constantly produced as by-products of cellular processes. A number of highly conserved antioxidant systems work to detoxify excess ROS and maintain redox homoeostasis. Since ROS play important roles in signal transduction processes, too much detoxification or too little ROS production will affect growth, development and differentiation. Excess ROS production or diminished antioxidant capacity will cause widespread cellular damage and can lead to senescence and cell death.
Figure 2
Figure 2. Hsp33: a chaperone specialized to protect against bleach stress
Exposure of organisms to the highly effective antimicrobial hypochlorous acid (HOCl) causes the oxidative unfolding of numerous cellular proteins. Hsp33, an ATP-independent redox-regulated chaperone, also undergoes oxidative protein unfolding upon bleach treatment. In the case of Hsp33, however, this unfolding is highly co-ordinated and instigated by intramolecular disulfide bond formation and zinc release. The concomitant conformational changes convert Hsp33 into an active chaperone. Once activated, Hsp33 binds to other unfolding proteins and prevents the irreversible loss of protein function (i.e. protein aggregation). This mode of action substantially increases bacterial bleach resistance.
Figure 3
Figure 3. Bacterial defence against bleach-induced protein unfolding
Proteins are the major targets of bleach damage in bacteria. To prevent bleach-induced protein unfolding and aggregation, bacteria employ at least two distinct chaperone systems: (i) the redox-regulated protein chaperone Hsp33, which is specifically activated by bleach, and (ii) the chemical chaperone polyP, which specifically accumulates during bleach stress conditions. PolyP is produced by PPK, which converts ATP into polyP. Bleach-induced accumulation of polyP is caused by the reversible oxidative inactivation of polyP phosphatase (PPX), which fails to hydrolyse the polymer into Pi. This mechanism explains the ATP-depletion phenotype observed in bleach-treated bacteria. red, reduced; ox, oxidized.

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