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      Control of mitochondrial superoxide production by reverse electron transport at complex I

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          Abstract

          The generation of mitochondrial superoxide (O 2 ˙̄) by reverse electron transport (RET) at complex I causes oxidative damage in pathologies such as ischemia reperfusion injury, but also provides the precursor to H 2O 2 production in physiological mitochondrial redox signaling. Here, we quantified the factors that determine mitochondrial O 2 ˙̄ production by RET in isolated heart mitochondria. Measuring mitochondrial H 2O 2 production at a range of proton-motive force (Δp) values and for several coenzyme Q (CoQ) and NADH pool redox states obtained with the uncoupler p-trifluoromethoxyphenylhydrazone, we show that O 2 ˙̄ production by RET responds to changes in O 2 concentration, the magnitude of Δp, and the redox states of the CoQ and NADH pools. Moreover, we determined how expressing the alternative oxidase from the tunicate Ciona intestinalis to oxidize the CoQ pool affected RET-mediated O 2 ˙̄ production at complex I, underscoring the importance of the CoQ pool for mitochondrial O 2 ˙̄ production by RET. An analysis of O 2 ˙̄ production at complex I as a function of the thermodynamic forces driving RET at complex I revealed that many molecules that affect mitochondrial reactive oxygen species production do so by altering the overall thermodynamic driving forces of RET, rather than by directly acting on complex I. These findings clarify the factors controlling RET-mediated mitochondrial O 2 ˙̄ production in both pathological and physiological conditions. We conclude that O 2 ˙̄ production by RET is highly responsive to small changes in Δp and the CoQ redox state, indicating that complex I RET represents a major mode of mitochondrial redox signaling.

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          Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

          Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I. DOI: http://dx.doi.org/10.7554/eLife.02242.001
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            Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes.

            The metabolism of aerobic organisms continuously produces reactive oxygen species. Although potentially toxic, these compounds also function in signaling. One important feature of signaling compounds is their ability to move between different compartments, e.g. to cross membranes. Here we present evidence that aquaporins can channel hydrogen peroxide (H2O2). Twenty-four aquaporins from plants and mammals were screened in five yeast strains differing in sensitivity toward oxidative stress. Expression of human AQP8 and plant Arabidopsis TIP1;1 and TIP1;2 in yeast decreased growth and survival in the presence of H2O2. Further evidence for aquaporin-mediated H2O2 diffusion was obtained by a fluorescence assay with intact yeast cells using an intracellular reactive oxygen species-sensitive fluorescent dye. Application of silver ions (Ag+), which block aquaporin-mediated water diffusion in a fast kinetics swelling assay, also reversed both the aquaporin-dependent growth repression and the H2O2-induced fluorescence. Our results present the first molecular genetic evidence for the diffusion of H2O2 through specific members of the aquaporin family.
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              Supercomplex assembly determines electron flux in the mitochondrial electron transport chain.

              The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                0021-9258
                1083-351X
                22 June 2018
                9 May 2018
                9 May 2018
                : 293
                : 25
                : 9869-9879
                Affiliations
                From the []Medical Research Council Mitochondrial Biology Unit, Hills Road, University of Cambridge, Cambridge CB2 0XY, United Kingdom,
                the [§ ]UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, United Kingdom,
                the []Faculty of Medicine and Life Sciences, University of Tampere, Tampere FI-33014, Finland, and
                the []Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany
                Author notes
                [2 ] To whom correspondence should be addressed: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, United Kingdom. Tel.: 44-1223-252-900; E-mail: mpm@ 123456mrc-mbu.cam.ac.uk .
                [1]

                Supported in part by the Great Ormond Street Hospital Children's Charity and the NIHR Biomedical Research Centre at Great Ormond Street Hospital.

                Edited by Ruma Banerjee

                Author information
                https://orcid.org/0000-0003-1115-9618
                Article
                RA118.003647
                10.1074/jbc.RA118.003647
                6016480
                29743240
                04300f5b-b21e-4099-8052-d1ed566d57ee
                © 2018 Robb et al.

                Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version free via Creative Commons CC-BY license.

                History
                : 23 April 2018
                : 8 May 2018
                Funding
                Funded by: RCUK | Medical Research Council (MRC) , open-funder-registry 10.13039/501100000265;
                Award ID: MC UU 00015/5
                Funded by: Wellcome Trust , open-funder-registry 10.13039/100004440;
                Award ID: 110159/Z/15/Z
                Categories
                Bioenergetics

                Biochemistry
                mitochondria,mitochondrial membrane potential,redox signaling,reactive oxygen species (ros),respiration,complex i,reverse electron transport,ret,coenzyme q,superoxide

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