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      Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

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          Ischaemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through generation of mitochondrial reactive oxygen species (ROS) 1- 5 . Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion 1, 3 . Here, we developed a comparative in vivo metabolomic analysis and unexpectedly identified widely conserved metabolic pathways responsible for mitochondrial ROS production during IR. We showed that selective accumulation of the citric acid cycle (CAC) intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase (SDH), which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Upon reperfusion, the accumulated succinate is rapidly re-oxidised by SDH, driving extensive ROS generation by reverse electron transport (RET) at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo IR injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of IR injury. Furthermore, these findings reveal a novel pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation upon subsequent reperfusion is a potential therapeutic target to decrease IR injury in a range of pathologies.

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          Most cited references 52

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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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            What is flux balance analysis?

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              Myocardial reperfusion injury.


                Author and article information

                1 October 2014
                05 November 2014
                20 November 2014
                20 May 2015
                : 515
                : 7527
                : 431-435
                [1 ]MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK
                [2 ]Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ, UK
                [3 ]MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
                [4 ]King’s College London, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital, London SE1 7EH, UK
                [5 ]Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Biology, University College London, Gower Street, London WC1E 6BT, UK
                [6 ]Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
                [7 ]Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
                [8 ]Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
                [9 ]School of Chemistry, University of Glasgow, Glasgow, G12 8TA, UK
                [10 ]Unit of Paediatric Surgery, UCL Institute of Child Health, London, WC1N 1EH, UK
                [11 ]University Department of Surgery and Cambridge NIHR Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
                Author notes
                Correspondence should be addressed to C.F ( CF366@ ), T.K ( tk382@ ) or M.P.M ( mpm@ )

                Author Contributions: E.T.C designed research, carried out biochemical experiments, analysed data from in vivo experiments and co-wrote the paper. T.K., V.R.P. and C.-H.H. designed and carried out the ex vivo and in vivo experiments. C.F. and E.G. designed and carried out mass spectrometry and metabolomics analyses with A.S.H.C. assisting. D.A. and M.J.S designed and carried out ex vivo perfused heart experiments. S.S, S.M.D, M.R.D., S.M.N, E.L.R. and P.S.B designed and carried out cell experiments. L.M.W, E.N.J.O. and R. S. designed and carried out brain experiments. A.J.D, S.R. and K.S.-P. designed and carried out kidney experiments. A.L. and R. C. H. carried out ROS analyses. S.E. carried out analyses. A.M.J helped with data interpretation. A.C.S, A.J.R & F.E. designed and performed bioinformatic analyses. E.T.C., T.K., C.F, and M.P.M directed the research and co-wrote the paper, with assistance from all other authors.


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