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Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress☆

a , b , *

Redox Biology

Elsevier

Oxidative stress, NADPH oxidases, Mitochondria, Peroxiporins, Redox regulation, H2O2

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      Abstract

      Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H2O2 in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H2O2 and on the role of H2O2 in redox signaling under physiological conditions (1–10 nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H2O2 (>100 nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H2O2 be assayed in the biological setting? What are the metabolic sources and sinks of H2O2? What is the role of H2O2 in redox signaling and oxidative stress?

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      Highlights

      •H2O2 is operative in redox sensing and redox signaling.•H2O2 reacts with metal centers and with sulfur/selenium compounds.•H2O2 links redox biology to phosphorylation/dephosphorylation.•Physiological (low-level, nM) steady-state of H2O2 is maintained in oxidative eustress.•Supraphysiological (pathological) level of H2O2 leads to oxidative distress.

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      Most cited references 110

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      How mitochondria produce reactive oxygen species

      The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2 •−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2 •− production within the matrix of mammalian mitochondria. The flux of O2 •− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2 •− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2 •− production is far lower. The generation of O2 •− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2 •− generation by mitochondria in vivo from O2 •−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2 •− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
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        The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

        For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.
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          Hydroperoxide metabolism in mammalian organs.

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            Author and article information

            Affiliations
            [a ]Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
            [b ]Leibniz Institute for Research in Environmental Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
            Author notes
            [* ]Correspondence address: Institut für Biochemie und Molekularbiologie I, Heinrich Heine Universität Düsseldorf, Universitätsstrasse 1, Geb. 22.03, D-40225 Düsseldorf, Germany. sies@ 123456uni-duesseldorf.de
            Contributors
            Journal
            Redox Biol
            Redox Biol
            Redox Biology
            Elsevier
            2213-2317
            05 January 2017
            April 2017
            05 January 2017
            : 11
            : 613-619
            28110218
            5256672
            S2213-2317(16)30319-6
            10.1016/j.redox.2016.12.035
            © 2017 The Authors

            This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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