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      Calcium and ROS: A mutual interplay

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          Abstract

          Calcium is an important second messenger involved in intra- and extracellular signaling cascades and plays an essential role in cell life and death decisions. The Ca 2+ signaling network works in many different ways to regulate cellular processes that function over a wide dynamic range due to the action of buffers, pumps and exchangers on the plasma membrane as well as in internal stores. Calcium signaling pathways interact with other cellular signaling systems such as reactive oxygen species (ROS). Although initially considered to be potentially detrimental byproducts of aerobic metabolism, it is now clear that ROS generated in sub-toxic levels by different intracellular systems act as signaling molecules involved in various cellular processes including growth and cell death. Increasing evidence suggests a mutual interplay between calcium and ROS signaling systems which seems to have important implications for fine tuning cellular signaling networks. However, dysfunction in either of the systems might affect the other system thus potentiating harmful effects which might contribute to the pathogenesis of various disorders.

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          Highlights

          • Calcium and ROS act as signaling molecules inside the cell and their pathways can interact.
          • The mutual interplay of calcium and ROS is required for the fine tuning of signaling.
          • Failure in the interplay results in dysfunction and pathologies.

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          Most cited references 171

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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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              Mitochondrial formation of reactive oxygen species.

               Julio Turrens (2003)
              The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2-*). Even though O2-* is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.
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                Author and article information

                Affiliations
                [a ]Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich, Germany
                [b ]DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
                [c ]Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
                [d ]Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
                Author notes
                [* ]Corresponding author at: Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany. Fax: +49 8 91281 2633.Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University MunichLazarettstr. 36Munich80636Germany goerlach@ 123456dhm.mhn.de
                [** ]Corresponding author at: Center for Molecular Medicine, Slovak Academy of Sciences, Vlarska 7, 831 01 Bratislava, Slovakia. Fax: +421 2 54773666.Center for Molecular Medicine, Slovak Academy of SciencesVlarska 7Bratislava831 01Slovakia olga.krizanova@ 123456savba.sk
                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                11 August 2015
                December 2015
                11 August 2015
                : 6
                : 260-271
                26296072 4556774 S2213-2317(15)00100-7 10.1016/j.redox.2015.08.010 REDOXD1500102
                © 2015 The Authors

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

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                Review Article

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