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The Role of Succinate and ROS in Reperfusion Injury – a Critical Appraisal

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The Role of Succinate and ROS in Reperfusion Injury – a Critical Appraisal Andrienko, T. N., Pasdois, P., Pereira, G. C., Ovens, M. J., & Halestrap, A. P. (2019). The role of succinate and ROS in reperfusion injury – A critical appraisal. Journal of Molecular and Cellular Cardiology, 110, 1-14. https://doi.org/10.1016/j.yjmcc.2017.06.016 Publisher's PDF, also known as Version of record License (if available): CC BY-NC-ND Link to published version (if available): 10.1016/j.yjmcc.2017.06.016 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Elsevier at https://doi.org/10.1016/j.yjmcc.2017.06.016 . Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ Journal of Molecular and Cellular Cardiology 110 (2017) 1–14 Contents lists available at ScienceDirect Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc Review article The role of succinate and ROS in reperfusion injury – Acriticalappraisal Tatyana N. Andrienko, Philippe Pasdois 1, Gonçalo C. Pereira, Matthew J. Ovens, Andrew P. Halestrap ⁎ School of Biochemistry and The Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK article info abstract Article history: We critically assess the proposal that succinate-fuelled reverse electron flow (REF) drives mitochondrial matrix Received 10 March 2017 superoxide production from Complex I early in reperfusion, thus acting as a key mediator of ischemia/reperfusion Received in revised form 14 June 2017 (IR) injury. Real-time surface fluorescence measurements of NAD(P)H and flavoprotein redox state suggest that Accepted 30 June 2017 conditions are unfavourable for REF during early reperfusion. Furthermore, rapid loss of succinate accumulated Available online 05 July 2017 during ischemia can be explained by its efflux rather than oxidation. Moreover, succinate accumulation during Keywords: ischemia is not attenuated by ischemic preconditioning (IP) despite powerful cardioprotection. In addition, mea- fl Succinate surement of intracellular reactive oxygen species (ROS) during reperfusion using surface uorescence and mito- Ischemia/reperfusion injury chondrial aconitase activity detected major increases in ROS only after mitochondrial permeability transition Heart pore (mPTP) opening was first detected. We conclude that mPTP opening is probably triggered initially by factors Mitochondria other than ROS, including increased mitochondrial [Ca2+]. However, IP only attenuates [Ca2+] increases later in Reactive oxygen species reperfusion, again after initial mPTP opening, implying that IP regulates mPTP opening through additional mech- Calcium anisms. One such is mitochondria-bound hexokinase 2 (HK2) which dissociates from mitochondria during ische- Permeability transition pore mia in control hearts but not those subject to IP. Indeed, there is a strong correlation between the extent of HK2 Hexokinase loss from mitochondria during ischemia and infarct size on subsequent reperfusion. Mechanisms linking HK2 dis- sociation to mPTP sensitisation remain to be fully established but several related processes have been implicated including VDAC1 oligomerisation, the stability of contact sites between the inner and outer membranes, cristae morphology, Bcl-2 family members and mitochondrial fission proteins such as Drp1. © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction............................................................... 2 2. DoesmitochondrialsuperoxideproductionprecedemPTPopeningduringreperfusion?............................. 2 2.1. ROSmeasurements......................................................... 2 2.1.1. Studiesusingisolatedcardiacmyocytes........................................... 2 2.1.2. Studiesusingtheperfusedheart.............................................. 3 2.2. EffectsofROSscavengers...................................................... 4 3. Assessing the evidence that succinate-driven reverse electron flowmediatessuperoxideproductionatComplexIduringreperfusion........ 4 3.1. TimecourseofComplexIoxidation................................................. 4 3.2. Succinatemeasurements...................................................... 5 3.3. Cardioprotectiveeffectsofsuccinatedehydrogenaseinhibition..................................... 5 3.4. CardioprotectiveeffectsofComplexIinhibitors............................................ 6 4. SuccinatestimulatesROSproductionfollowingmPTPopening........................................ 7 Abbreviations: 5-cH2DCFDA, 5-carboxy-2′,7′dichlorodihydrofluorescein diacetate; ANT, adenine nucleotide translocase; Bad, Bcl-2-associated death promoter; Bak, Bcl-2 homologous antagonist/killer; Bax, Bcl-2-like protein 4; Bcl-2, B cell lymphoma 2; BCECF, 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein; Bcl-xL, B-cell lymphoma-extra large; Bid, BH3 interacting-domain death agonist; CK, creatine kinase; CrP, creatine phosphate; CsA, cyclosporine A; Cyp-D, cyclophilin D; DHE, dihydroethidium; Drp1, dynamin-related protein 1; G- 6-P, glucose-6-phosphate; GSK3β, glycogen synthase kinase 3β; HK, hexokinase; IF1, ATP synthase inhibitor factor 1; IMM, inner mitochondrial membrane; IP, ischemic preconditioning; IR, ischemia/reperfusion; Mdivi-1, mitochondrial division inhibitor 1; LS, light scattering; MCU, mitochondrial calcium uniporter; MitoPY1, Mitochondria Peroxy- Yellow 1; mPTP, mitochondrial permeability transition pore; NCLX, Na+/Ca2+ exchanger; OMM, outer mitochondrial membrane; PCr, phosphocreatine; PKCε, protein kinase Cε; pmf, proton motive force; PO1, Peroxy-Orange 1; REF, reverse electron flow; ROS, reactive oxygen species; SOD, superoxide dismutase; VDAC, voltage-dependent anion channel. ⁎ Corresponding author. E-mail address: [email protected] (A.P. Halestrap). 1 Current address: IHU-LIRYC, Inserm U1045, Université de Bordeaux, 33600 Pessac, France. http://dx.doi.org/10.1016/j.yjmcc.2017.06.016 0022-2828/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2 T.N. Andrienko et al. / Journal of Molecular and Cellular Cardiology 110 (2017) 1–14 5. AlternativetriggersformPTPopeningearlyinreperfusion.......................................... 8 5.1. The role of Ca2+ .......................................................... 8 5.2. Theroleofmitochondria-boundhexokinase2............................................. 8 5.3. Theroleofmitochondrialcontactsitesandcristaemorphology..................................... 9 5.4. The role of mitochondrial fission................................................... 9 6. Conclusions................................................................11 Sourcesoffunding...............................................................11 Disclosures..................................................................11 Acknowledgements..............................................................11 References...................................................................11 1. Introduction initiates mPTP opens on reperfusion and that IP attenuates other factors that sensitise the mPTP to [Ca2+], including the well-established disso- It is now widely accepted that the irreversible injury of the heart ciation of hexokinase 2 (HK2) from its mitochondrial binding site that which occurs during reperfusion after a prolonged period of ischemia occurs during ischemia [27–29]. However, substantial ROS production is mediated, at least in part, by opening of the mitochondrial permeabil- does occur later in reperfusion as a consequence of initial mPTP open- ity transition pore (mPTP) [1,2]. This starts after about 2 min of reperfu- ing, and this leads to further pore opening and an expanding area of ne- sion [3,4] and coincides with the intracellular pH (pHi) returning to pre- crotic cell death that forms the infarct. Cardioprotective protocols such ischemic values from the low values (b6.5) that are reached after as IP prevent HK2 loss from mitochondria during ischemia and so pre- prolonged ischemia and which inhibit mPTP opening [5]. Opening of vent both phases of mPTP opening. the mPTP not only compromises cellular bioenergetics, thus impairing the re-establishment of pre-ischemic levels of ions such as calcium, 2. Does mitochondrial superoxide production precede mPTP open- but also causes mitochondria to release reactive oxygen species (ROS) ing during reperfusion? [6,7]. The resulting increases in ROS and [Ca2+] induce further mPTP opening and bioenergetic compromise leading to a spreading wave of 2.1. ROS measurements necrotic cell death that produces the infarct [1,8]. Pharmacological inhi- bition of mPTP opening by cyclosporin A (CsA) [9], sanglifehrin A [10] or The American Heart Association has recently published a “Scientific cinnamic anilides [11] can protect hearts from ischemia/reperfusion Statement” on the measurement of ROS species which provides a com- (IR) injury as can ischemic preconditioning (IP) and post-conditioning, prehensive review of the available methods, their limitations and what
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