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      Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism

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          Abstract

          Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

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          Most cited references214

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          HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

          HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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            Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.

            Multicellular organisms initiate adaptive responses when oxygen (O(2)) availability decreases, but the underlying mechanism of O(2) sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1 alpha and HIF-2 alpha and that an increase in reactive oxygen species (ROS) links this complex to HIF-alpha stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1 alpha stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O(2) sensors and signal hypoxic HIF-1 alpha and HIF-2 alpha stabilization by releasing ROS to the cytosol.
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              ATM activation by oxidative stress.

              The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
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                Author and article information

                Contributors
                +31-24-3614589 , Werner.Koopman@radboudumc.nl
                Journal
                Arch Toxicol
                Arch. Toxicol
                Archives of Toxicology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-5761
                1432-0738
                6 June 2015
                6 June 2015
                2015
                : 89
                : 8
                : 1209-1226
                Affiliations
                [ ]Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RUMC), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
                [ ]Department of Human and Animal Physiology, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands
                Article
                1520
                10.1007/s00204-015-1520-y
                4508370
                26047665
                07e92ef3-a299-4ba6-8d67-abf64b41eeff
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 13 April 2015
                : 27 April 2015
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2015

                Toxicology
                glucose,glut1,glut4,mitochondria,ros,oxidative stress
                Toxicology
                glucose, glut1, glut4, mitochondria, ros, oxidative stress

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