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Mitochondrial Calcium and Ischemia: Reperfusion Injury in Heart

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Mitochondria and Cell Death

Abstract

Cardiac ischemia (I) caused by coronary artery occlusion or by significantly reduced blood flow may be lethal if not treated. However, ischemia “preconditioning” may provide benefit to future ischemic insults. The treatment for ischemia itself (i.e., reperfusion, R) can have significant adverse effects. For example, reperfusion may underlie myocardial cell metabolic and Ca2+ signaling dysfunction in these robust but non-regenerating contractile cells. This chapter reviews and discusses the experimental evidence that links mitochondrial dysfunction or mitochondrial collapse to cardiomyocyte cell death as primary cause. Pathophysiological changes in the Ca2+ level in the mitochondrial matrix ([Ca2+]m) appear to be pivotal in triggering the collapse. Nevertheless, this and other aspects of the I-R process are not fully understood and are under active investigation as highlighted here. We have divided the presentation into four parts. First, our state-of-the art quantitative understanding of Ca2+ movement across the mitochondrial inner membrane (IMM) is discussed. The presentation focuses specifically on how cytosolic [Ca2+]i signals affect [Ca2+]m and our new understanding of this process that arises in the context of recent molecular characterizations of the transport systems that mediate Ca2+ fluxes across the IMM. Specific emphasis is placed on the mitochondrial Ca2+ uniporter (MCU) and the mitochondrial Na+/Ca2+ exchanger (NCLX). Second, the ionic and energetic imbalances that develop during ischemia are identified and discussed with respect to how these imbalances progressively degrade the ability of cardiomyocytes to regulate [Ca2+]i and [Ca2+]m. Third, the altered regulation of [Ca2+]m during the ischemia is presented and this dysregulation of [Ca2+]m is discussed as a predisposing component of the eventual mitochondrial collapse on reperfusion. Finally, emerging evidence suggests that the mitochondrial collapse is due to a catastrophic activation of mitochondrial permeability transition pores (mPTPs). Controversial molecular aspects of mPTP activation are also highlighted and discussed along with the putative regulation by pathological [Ca2+]m and the possible beneficial consequences of therapeutic control of mPTP behavior.

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References

  • Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Li H, Signore AP, Smith PJS, Gribkoff VK, Jonas EA (2014a) The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole. Mol Pharmacol. doi:10.1124/mol.114.095661

    PubMed  Google Scholar 

  • Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park H-A, Licznerski P, Li H, Nabili P, Hockensmith K, Graham M, Porter GA, Jonas EA (2014b) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 111:10580–10585. doi:10.1073/pnas.1401591111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen DG, Orchard CH (1983) Intracellular calcium concentration during hypoxia and metabolic inhibition in mammalian ventricular muscle. J Physiol Lond 339:107–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen DG, Xiao X-H (2003) Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion. Cardiovasc Res 57:934–941

    Article  CAS  PubMed  Google Scholar 

  • Allen DG, Morris PG, Orchard CH, Pirolo JS (1985) A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis. J Physiol Lond 361:185–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen DG, Lee JA, Smith GL (1989) The consequences of simulated ischaemia on intracellular Ca2+ and tension in isolated ferret ventricular muscle. J Physiol Lond 410:297–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allshire A, Piper HM, Cuthbertson KS, Cobbold PH (1987) Cytosolic free Ca2+ in single rat heart cells during anoxia and reoxygenation. Biochem J 244:381–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Nasser I, Crompton M (1986) The reversible Ca2+-induced permeabilization of rat liver mitochondria. Biochem J 239:19–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson SE, Dickinson CZ, Liu H, Cala PM (1996) Effects of Na-K-2Cl cotransport inhibition on myocardial Na and Ca during ischemia and reperfusion. Am J Physiol 270:C608–C618

    CAS  PubMed  Google Scholar 

  • Andrews ZB, Diano S, Horvath TL (2005) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6:829–840. doi:10.1038/nrn1767

    Article  CAS  PubMed  Google Scholar 

  • Appleyard RF, Cohn LH (1993) Myocardial stunning and reperfusion injury in cardiac surgery. J Card Surg 8:316–324

    Article  CAS  PubMed  Google Scholar 

  • Argaud L, Gateau-Roesch O, Chalabreysse L, Gomez L, Loufouat J, Thivolet-Béjui F, Robert D, Ovize M (2004) Preconditioning delays Ca2+-induced mitochondrial permeability transition. Cardiovasc Res 61:115–122

    Article  CAS  PubMed  Google Scholar 

  • Argaud L, Gateau-Roesch O, Muntean D, Chalabreysse L, Loufouat J, Robert D, Ovize M (2005) Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 38:367–374. doi:10.1016/j.yjmcc.2004.12.001

    Article  CAS  PubMed  Google Scholar 

  • Baines CP (2009) The molecular composition of the mitochondrial permeability transition pore. J Mol Cell Cardiol 46:850–857. doi:10.1016/j.yjmcc.2009.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baines CP (2011) How and when do myocytes die during ischemia and reperfusion: the late phase. J Cardiovasc Pharmacol Ther 16:239–243. doi:10.1177/1074248411407769

    Article  CAS  PubMed  Google Scholar 

  • Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662. doi:10.1038/nature03434

    Article  CAS  PubMed  Google Scholar 

  • Barry WH, Peeters GA, Rasmussen CA, Cunningham MJ (1987) Role of changes in [Ca2+]i in energy deprivation contracture. Circ Res 61:726–734

    Article  CAS  PubMed  Google Scholar 

  • Bassani JW, Bassani RA, Bers DM (1994) Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol Lond 476:279–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baxter GF, Ferdinandy P (2001) Delayed preconditioning of myocardium: current perspectives. Basic Res Cardiol 96:329–344

    Article  CAS  PubMed  Google Scholar 

  • Beatrice MC, Palmer JW, Pfeiffer DR (1980) The relationship between mitochondrial membrane permeability, membrane potential, and the retention of Ca2+ by mitochondria. J Biol Chem 255:8663–8671

    CAS  PubMed  Google Scholar 

  • Bernardi P, von Stockum S (2012) The permeability transition pore as a Ca(2+) release channel: new answers to an old question. Cell Calcium 52:22–27. doi:10.1016/j.ceca.2012.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabo I, Zoratti M (1992) Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J Biol Chem 267:2934–2939

    CAS  PubMed  Google Scholar 

  • Blaustein MP, Lederer WJ (1999) Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763–854

    CAS  PubMed  Google Scholar 

  • Bolli R, Marbán E (1999) Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79:609–634

    CAS  PubMed  Google Scholar 

  • Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683. doi:10.4161/cc.23599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyman L, Hagen BM, Giladi M, Hiller R, Lederer WJ, Khananshvili D (2011) Proton-sensing Ca2+ binding domains regulate the cardiac Na+/Ca2+ exchanger. J Biol Chem 286:28811–28820. doi:10.1074/jbc.M110.214106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyman L, Williams GSB, Khananshvili D, Sekler I, Lederer WJ (2013) NCLX: the mitochondrial sodium calcium exchanger. J Mol Cell Cardiol 59:205–213. doi:10.1016/j.yjmcc.2013.03.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyman L, Chikando AC, Williams GSB, Khairallah RJ, Kettlewell S, Ward CW, Smith GL, Kao JPY, Lederer WJ (2014) Calcium movement in cardiac mitochondria. Biophys J 107:1289–1301. doi:10.1016/j.bpj.2014.07.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braasch W, Gudbjarnason S, Puri PS, Ravens KG, Bing RJ (1968) Early changes in energy metabolism in the myocardium following acute coronary artery occlusion in anesthetized dogs. Circ Res 23:429–438

    Article  CAS  PubMed  Google Scholar 

  • Brandes R, Maier LS, Bers DM (1998) Regulation of mitochondrial [NADH] by cytosolic [Ca2+] and work in trabeculae from hypertrophic and normal rat hearts. Circ Res 82:1189–1198

    Article  CAS  PubMed  Google Scholar 

  • Butwell NB, Ramasamy R, Lazar I, Sherry AD, Malloy CR (1993) Effect of lidocaine on contracture, intracellular sodium, and pH in ischemic rat hearts. Am J Physiol 264:H1884–H1889

    CAS  PubMed  Google Scholar 

  • Carafoli E, Lehninger AL (1971) A survey of the interaction of calcium ions with mitochondria from different tissues and species. Biochem J 122:681–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carraro M, Giorgio V, Sileikyte J, Sartori G, Forte M, Lippe G, Zoratti M, Szabò I, Bernardi P (2014) Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition. J Biol Chem. doi:10.1074/jbc.C114.559633

    PubMed  PubMed Central  Google Scholar 

  • Chen Y-R, Zweier JL (2014) Cardiac mitochondria and reactive oxygen species generation. Circ Res 114:524–537. doi:10.1161/CIRCRESAHA.114.300559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen EP, Bittner HB, Davis RD, Folz RJ, Van Trigt P (1996) Extracellular superoxide dismutase transgene overexpression preserves postischemic myocardial function in isolated murine hearts. Circulation 94:II412–II417

    CAS  PubMed  Google Scholar 

  • Chen Z, Siu B, Ho YS, Vincent R, Chua CC, Hamdy RC, Chua BH (1998) Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. J Mol Cell Cardiol 30:2281–2289. doi:10.1006/jmcc.1998.0789

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Oberley TD, Ho Y, Chua CC, Siu B, Hamdy RC, Epstein CJ, Chua BH (2000) Overexpression of CuZnSOD in coronary vascular cells attenuates myocardial ischemia/reperfusion injury. Free Radic Biol Med 29:589–596

    Article  CAS  PubMed  Google Scholar 

  • Chinopoulos C, Adam-Vizi V (2012) Modulation of the mitochondrial permeability transition by cyclophilin D: moving closer to F(0)-F(1) ATP synthase? Mitochondrion 12:41–45. doi:10.1016/j.mito.2011.04.007

    Article  CAS  PubMed  Google Scholar 

  • Choy IO, Schepkin VD, Budinger TF, Obayashi DY, Young JN, DeCampli WM (1997) Effects of specific sodium/hydrogen exchange inhibitor during cardioplegic arrest. Ann Thorac Surg 64:94–99

    Article  CAS  PubMed  Google Scholar 

  • Clarke SJ, Khaliulin I, Das M, Parker JE, Heesom KJ, Halestrap AP (2008) Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res 102:1082–1090. doi:10.1161/CIRCRESAHA.107.167072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cobbe SM, Poole-Wilson PA (1980) The time of onset and severity of acidosis in myocardial ischaemia. J Mol Cell Cardiol 12:745–760

    Article  CAS  PubMed  Google Scholar 

  • Cobbold PH, Bourne PK (1984) Aequorin measurements of free calcium in single heart cells. Nature 312:444–446

    Article  CAS  PubMed  Google Scholar 

  • Correll RN, Molkentin JD (2013) CaMKII does it again: even the mitochondria cannot escape its influence. Circ Res 112:1208–1211. doi:10.1161/CIRCRESAHA.113.301263

    Article  CAS  PubMed  Google Scholar 

  • Cortassa S, Aon MA, Marbán E, Winslow RL, O'Rourke B (2003) An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J 84:2734–2755. doi:10.1016/S0006-3495(03)75079-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couper GS, Weiss J, Hiltbrand B, Shine KI (1984) Extracellular pH and tension during ischemia in the isolated rabbit ventricle. Am J Physiol 247:H916–H927

    CAS  PubMed  Google Scholar 

  • Crake T, Crean PA, Shapiro LM, Rickards AF, Poole-Wilson PA (1987) Coronary sinus pH during percutaneous transluminal coronary angioplasty: early development of acidosis during myocardial ischaemia in man. Br Heart J 58:110–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crompton M, Costi A, Hayat L (1987) Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J 245:915–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crompton M, Ellinger H, Costi A (1988) Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 255:357–360

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cross HR, RADDA GK, Clarke K (1995) The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study. Magn Reson Med 34:673–685

    Article  CAS  PubMed  Google Scholar 

  • Das DK, Maulik N (2006) Cardiac genomic response following preconditioning stimulus. Cardiovasc Res 70:254–263. doi:10.1016/j.cardiores.2006.02.023

    Article  CAS  PubMed  Google Scholar 

  • Di Lisa F, Menabò R, Canton M, Barile M, Bernardi P (2001) Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem 276:2571–2575. doi:10.1074/jbc.M006825200

    Article  PubMed  Google Scholar 

  • Dizon J, Burkhoff D, Tauskela J, Whang J, Cannon P, Katz J (1998) Metabolic inhibition in the perfused rat heart: evidence for glycolytic requirement for normal sodium homeostasis. Am J Physiol 274:H1082–H1089

    CAS  PubMed  Google Scholar 

  • Drago I, De Stefani D, Rizzuto R, Pozzan T (2012) Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes. Proc Natl Acad Sci U S A 109:12986–12991. doi:10.1073/pnas.1210718109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn RB, Griggs DM (1975) Transmural gradients in ventricular tissue metabolites produced by stopping coronary blood flow in the dog. Circ Res 37:438–445

    Article  CAS  PubMed  Google Scholar 

  • Edwards RJ, Saurin AT, Rakhit RD, Marber MS (2000) Therapeutic potential of ischaemic preconditioning. Br J Clin Pharmacol 50:87–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eigel BN, Hadley RW (1999) Contribution of the Na(+) channel and Na(+)/H(+) exchanger to the anoxic rise of [Na(+)] in ventricular myocytes. Am J Physiol 277:H1817–H1822

    CAS  PubMed  Google Scholar 

  • Elrod JW, Molkentin JD (2013) Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore. Circ J 77:1111–1122

    Article  CAS  PubMed  Google Scholar 

  • Fieni F, Lee SB, Jan YN, Kirichok Y (2012) Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat Commun 3:1317. doi:10.1038/ncomms2325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fieni F, Johnson DE, Hudmon A, Kirichok Y (2014) Mitochondrial Ca2+ uniporter and CaMKII in heart. Nature 513:E1–E2. doi:10.1038/nature13626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franzini-Armstrong C (2007) ER-mitochondria communication. How privileged? Physiology (Bethesda) 22:261–268. doi:10.1152/physiol.00017.2007

    Article  CAS  Google Scholar 

  • Fuller W, Parmar V, Eaton P, Bell JR, Shattock MJ (2003) Cardiac ischemia causes inhibition of the Na/K ATPase by a labile cytosolic compound whose production is linked to oxidant stress. Cardiovasc Res 57:1044–1051

    Article  CAS  PubMed  Google Scholar 

  • Fuller W, Eaton P, Bell JR, Shattock MJ (2004) Ischemia-induced phosphorylation of phospholemman directly activates rat cardiac Na/K-ATPase. FASEB J 18:197–199. doi:10.1096/fj.03-0213fje

    CAS  PubMed  Google Scholar 

  • Gabel SA, Cross HR, London RE, Steenbergen C, Murphy E (1997) Decreased intracellular pH is not due to increased H+ extrusion in preconditioned rat hearts. Am J Physiol 273:H2257–H2262

    CAS  PubMed  Google Scholar 

  • García-Rivas Gde J, Carvajal K, Correa F, Zazueta C (2006) Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol 149:829–837. doi:10.1038/sj.bjp.0706932

    Article  PubMed  CAS  Google Scholar 

  • Garlick PB, RADDA GK, Seeley PJ (1979) Studies of acidosis in the ischaemic heart by phosphorus nuclear magnetic resonance. Biochem J 184:547–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gauthier LD, Greenstein JL, Winslow RL (2012) Toward an integrative computational model of the Guinea pig cardiac myocyte. Front Physiol 3:244. doi:10.3389/fphys.2012.00244

    Article  PubMed  PubMed Central  Google Scholar 

  • Gevers W (1977) Generation of protons by metabolic processes in heart cells. J Mol Cell Cardiol 9:867–874

    Article  CAS  PubMed  Google Scholar 

  • Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabò I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110:5887–5892. doi:10.1073/pnas.1217823110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glancy B, Balaban RS (2012) Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 51:2959–2973. doi:10.1021/bi2018909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez L, Thibault H, Gharib A, Dumont J-M, Vuagniaux G, Scalfaro P, Derumeaux G, Ovize M (2007) Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol 293:H1654–H1661. doi:10.1152/ajpheart.01378.2006

    Article  CAS  PubMed  Google Scholar 

  • Graier WF, Trenker M, Malli R (2008) Mitochondrial Ca2+, the secret behind the function of uncoupling proteins 2 and 3? Cell Calcium 44:36–50. doi:10.1016/j.ceca.2008.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffiths EJ, Halestrap AP (1993) Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 25:1461–1469. doi:10.1006/jmcc.1993.1162

    Article  CAS  PubMed  Google Scholar 

  • Griffiths EJ, Halestrap AP (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 307(Pt 1):93–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gudbjarnason S, Mathes P, Ravens KG (1970) Functional compartmentation of ATP and creatine phosphate in heart muscle. J Mol Cell Cardiol 1:325–339

    Article  CAS  PubMed  Google Scholar 

  • Haigney MC, Lakatta EG, Stern MD, Silverman HS (1994) Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation 90:391–399

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP (1991) Calcium-dependent opening of a non-specific pore in the mitochondrial inner membrane is inhibited at pH values below 7. Implications for the protective effect of low pH against chemical and hypoxic cell damage. Biochem J 278(Pt 3):715–719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halestrap AP (2006) Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34:232–237. doi:10.1042/BST20060232

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP (2009) Mitochondria and reperfusion injury of the heart--a holey death but not beyond salvation. J Bioenerg Biomembr 41:113–121. doi:10.1007/s10863-009-9206-x

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP (2014) The C ring of the F1Fo ATP synthase forms the mitochondrial permeability transition pore: a critical appraisal. Mol Cell Oncol. doi:10.3389/fonc.2014.00234

    Google Scholar 

  • Halestrap AP, Richardson AP (2014) The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2014.08.018

    PubMed  Google Scholar 

  • Hartmann M, Decking UK (1999) Blocking Na(+)-H+ exchange by cariporide reduces Na(+)-overload in ischemia and is cardioprotective. J Mol Cell Cardiol 31:1985–1995. doi:10.1006/jmcc.1999.1029

    Article  CAS  PubMed  Google Scholar 

  • Hausenloy DJ, Duchen MR, Yellon DM (2003) Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 60:617–625

    Article  CAS  PubMed  Google Scholar 

  • Hausenloy DJ, Yellon DM, Mani-Babu S, Duchen MR (2004) Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol Heart Circ Physiol 287:H841–H849. doi:10.1152/ajpheart.00678.2003

    Article  CAS  PubMed  Google Scholar 

  • Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175. doi:10.1016/S0140-6736(12)60916-7

    Article  PubMed  Google Scholar 

  • Hirche H, Franz C, Bös L, Bissig R, Lang R, Schramm M (1980) Myocardial extracellular K+ and H+ increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion in pigs. J Mol Cell Cardiol 12:579–593

    Article  CAS  PubMed  Google Scholar 

  • Hunter FE, Ford L (1955) Inactivation of oxidative and phosphorylative systems in mitochondria by preincubation with phosphate and other ions. J Biol Chem 216:357–369

    CAS  PubMed  Google Scholar 

  • Hunter DR, Haworth RA (1979) The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195:453–459

    Article  CAS  PubMed  Google Scholar 

  • Imahashi K, Pott C, Goldhaber JI, Steenbergen C, Philipson KD, Murphy E (2005) Cardiac-specific ablation of the Na+-Ca2+ exchanger confers protection against ischemia/reperfusion injury. Circ Res 97:916–921. doi:10.1161/01.RES.0000187456.06162.cb

    Article  CAS  PubMed  Google Scholar 

  • Isenberg G, Han S, Schiefer A, Wendt-Gallitelli MF (1993) Changes in mitochondrial calcium concentration during the cardiac contraction cycle. Cardiovasc Res 27:1800–1809

    Article  CAS  PubMed  Google Scholar 

  • Jacobus WE, Pores IH, Lucas SK, Weisfeldt ML, Flaherty JT (1982) Intracellular acidosis and contractility in the normal and ischemic heart as examined by 31P NMR. J Mol Cell Cardiol 14(Suppl 3):13–20

    Article  CAS  PubMed  Google Scholar 

  • Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KHH, Halestrap AP (2003) Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol Lond 549:513–524. doi:10.1113/jphysiol.2003.034231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG, Karmazyn M (2008) NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res 77:416–424. doi:10.1093/cvr/cvm039

    Article  CAS  PubMed  Google Scholar 

  • Jennings RB, Reimer KA (1981) Lethal myocardial ischemic injury. Am J Pathol 102:241–255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jennings RB, Reimer KA (1991) The cell biology of acute myocardial ischemia. Annu Rev Med 42:225–246. doi:10.1146/annurev.me.42.020191.001301

    Article  CAS  PubMed  Google Scholar 

  • Jennings RB, Sommers HM, Herdson PB, Kaltenbach JP (1969) Ischemic injury of myocardium. Ann N Y Acad Sci 156:61–78

    Article  CAS  PubMed  Google Scholar 

  • Jennings RB, Hawkins HK, Lowe JE, Hill ML, Klotman S, Reimer KA (1978a) Relation between high energy phosphate and lethal injury in myocardial ischemia in the dog. Am J Pathol 92:187–214

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jennings RB, Shen AC, Hill ML, Ganote CE, Herdson PB (1978b) Mitochondrial matrix densities in myocardial ischemia and autolysis. Exp Mol Pathol 29:55–65

    Article  CAS  PubMed  Google Scholar 

  • Jennings RB, Murry CE, Steenbergen C, Reimer KA (1990) Development of cell injury in sustained acute ischemia. Circulation 82:II2–II12

    CAS  PubMed  Google Scholar 

  • Joiner M-LA, Koval OM, Li J, He BJ, Allamargot C, Gao Z, Luczak ED, Hall DD, Fink BD, Chen B, Yang J, Moore SA, Scholz TD, Strack S, Mohler PJ, Sivitz WI, Song L-S, Anderson ME (2012) CaMKII determines mitochondrial stress responses in heart. Nature 491:269–273. doi:10.1038/nature11444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karch J, Molkentin JD (2014) Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 111:10396–10397. doi:10.1073/pnas.1410104111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khaliulin I, Schwalb H, Wang P, Houminer E, Grinberg L, Katzeff H, Borman JB, Powell SR (2004) Preconditioning improves postischemic mitochondrial function and diminishes oxidation of mitochondrial proteins. Free Radic Biol Med 37:1–9. doi:10.1016/j.freeradbiomed.2004.04.017

    Article  CAS  PubMed  Google Scholar 

  • Kihara Y, Grossman W, Morgan JP (1989) Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res 65:1029–1044

    Article  CAS  PubMed  Google Scholar 

  • Kinnally KW, Campo ML, Tedeschi H (1989) Mitochondrial channel activity studied by patch-clamping mitoplasts. J Bioenerg Biomembr 21:497–506

    Article  CAS  PubMed  Google Scholar 

  • Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364. doi:10.1038/nature02246

    Article  CAS  PubMed  Google Scholar 

  • Kitakaze M, Takashima S, Funaya H, Minamino T, Node K, Shinozaki Y, Mori H, Hori M (1997) Temporary acidosis during reperfusion limits myocardial infarct size in dogs. Am J Physiol 272:H2071–H2078

    CAS  PubMed  Google Scholar 

  • Kloner RA, Jennings RB (2001a) Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation 104:2981–2989

    Article  CAS  PubMed  Google Scholar 

  • Kloner RA, Jennings RB (2001b) Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. Circulation 104:3158–3167

    Article  CAS  PubMed  Google Scholar 

  • Kloner RA, Rezkalla SH (2006) Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 70:297–307. doi:10.1016/j.cardiores.2006.01.012

    Article  CAS  PubMed  Google Scholar 

  • Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465. doi:10.1038/nature02229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kübler W, Spieckermann PG (1970) Regulation of glycolysis in the ischemic and the anoxic myocardium. J Mol Cell Cardiol 1:351–377

    Article  PubMed  Google Scholar 

  • Ladilov YV, Balser-Schäfer C, Haffner S, Maxeiner H, Piper HM (1999) Pretreatment with PKC activator protects cardiomyocytes against reoxygenation-induced hypercontracture independently of Ca2+ overload. Cardiovasc Res 43:408–416

    Article  CAS  PubMed  Google Scholar 

  • Lederer WJ, Nichols CG, Smith GL (1989) The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition. J Physiol Lond 413:329–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HC, Smith N, Mohabir R, Clusin WT (1987) Cytosolic calcium transients from the beating mammalian heart. Proc Natl Acad Sci U S A 84:7793–7797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HC, Mohabir R, Smith N, Franz MR, Clusin WT (1988) Effect of ischemia on calcium-dependent fluorescence transients in rabbit hearts containing indo 1. Correlation with monophasic action potentials and contraction. Circulation 78:1047–1059

    Article  CAS  PubMed  Google Scholar 

  • Lombardi A, Grasso P, Moreno M, de Lange P, Silvestri E, Lanni A, Goglia F (2008) Interrelated influence of superoxides and free fatty acids over mitochondrial uncoupling in skeletal muscle. Biochim Biophys Acta 1777:826–833. doi:10.1016/j.bbabio.2008.04.019

    Article  CAS  PubMed  Google Scholar 

  • Lu X, Ginsburg KS, Kettlewell S, Bossuyt J, Smith GL, Bers DM (2013) Measuring local gradients of intramitochondrial [Ca(2+)] in cardiac myocytes during sarcoplasmic reticulum Ca(2+) release. Circ Res 112:424–431. doi:10.1161/CIRCRESAHA.111.300501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, O'Rourke B (2006) Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ Res 99:172–182. doi:10.1161/01.RES.0000232546.92777.05

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marbán E, Kitakaze M, Kusuoka H, Porterfield JK, Yue DT, Chacko VP (1987) Intracellular free calcium concentration measured with 19F NMR spectroscopy in intact ferret hearts. Proc Natl Acad Sci U S A 84:6005–6009

    Article  PubMed  PubMed Central  Google Scholar 

  • McCormack JG, Denton RM (1993a) The role of intramitochondrial Ca2+ in the regulation of oxidative phosphorylation in mammalian tissues. Biochem Soc Trans 21(Pt 3):793–799

    Article  CAS  PubMed  Google Scholar 

  • McCormack JG, Denton RM (1993b) Mitochondrial Ca2+ transport and the role of intramitochondrial Ca2+ in the regulation of energy metabolism. Dev Neurosci 15:165–173

    Article  CAS  PubMed  Google Scholar 

  • Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, Ruhparwar A, Wahlers T, Hoppe UC (2009) Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119:2435–2443. doi:10.1161/CIRCULATIONAHA.108.835389

    Article  CAS  PubMed  Google Scholar 

  • Miyata H, Lakatta EG, Stern MD, Silverman HS (1992) Relation of mitochondrial and cytosolic free calcium to cardiac myocyte recovery after exposure to anoxia. Circ Res 71:605–613

    Article  CAS  PubMed  Google Scholar 

  • Murphy E, Allen DG (2009) Why did the NHE inhibitor clinical trials fail? J Mol Cell Cardiol 46:137–141. doi:10.1016/j.yjmcc.2008.09.715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy E, Eisner DA (2009) Regulation of intracellular and mitochondrial sodium in health and disease. Circ Res 104:292–303. doi:10.1161/CIRCRESAHA.108.189050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy E, Steenbergen C (2011) What makes the mitochondria a killer? Can we condition them to be less destructive? Biochim Biophys Acta 1813:1302–1308. doi:10.1016/j.bbamcr.2010.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy E, Jacob R, Lieberman M (1985) Cytosolic free calcium in chick heart cells. Its role in cell injury. J Mol Cell Cardiol 17:221–231

    Article  CAS  PubMed  Google Scholar 

  • Murphy E, Perlman M, London RE, Steenbergen C (1991) Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res 68:1250–1258

    Article  CAS  PubMed  Google Scholar 

  • Murphy E, Cross H, Steenbergen C (1999) Sodium regulation during ischemia versus reperfusion and its role in injury. Circ Res 84:1469–1470

    Article  CAS  PubMed  Google Scholar 

  • Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658. doi:10.1038/nature03317

    Article  CAS  PubMed  Google Scholar 

  • Nazareth W, Yafei N, Crompton M (1991) Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol 23:1351–1354

    Article  CAS  PubMed  Google Scholar 

  • Neely JR, Rovetto MJ, Whitmer JT, Morgan HE (1973) Effects of ischemia on function and metabolism of the isolated working rat heart. Am J Physiol 225:651–658

    CAS  PubMed  Google Scholar 

  • Neely JR, Whitmer JT, Rovetto MJ (1975) Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts. Circ Res 37:733–741

    Article  CAS  PubMed  Google Scholar 

  • Negretti N, Varro A, Eisner DA (1995) Estimate of net calcium fluxes and sarcoplasmic reticulum calcium content during systole in rat ventricular myocytes. J Physiol Lond 486(Pt 3):581–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nicholls D, Akerman K (1982) Mitochondrial calcium transport. Biochim Biophys Acta 683:57–88

    Article  CAS  PubMed  Google Scholar 

  • Nichols CG, Lederer WJ (1990a) The regulation of ATP-sensitive K+ channel activity in intact and permeabilized rat ventricular myocytes. J Physiol Lond 423:91–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nichols CG, Lederer WJ (1990b) The role of ATP in energy-deprivation contractures in unloaded rat ventricular myocytes. Can J Physiol Pharmacol 68:183–194

    Article  CAS  PubMed  Google Scholar 

  • Pacher P, Csordás P, Schneider T, Hajnóczky G (2000) Quantification of calcium signal transmission from sarco-endoplasmic reticulum to the mitochondria. J Physiol Lond 529(Pt 3):553–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili D, Sekler I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107:436–441. doi:10.1073/pnas.0908099107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, Fergusson MM, Rovira II, Allen M, Springer DA, Aponte AM, Gucek M, Balaban RS, Murphy E, Finkel T (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 15:1464–1472. doi:10.1038/ncb2868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park CO, Xiao XH, Allen DG (1999) Changes in intracellular Na+ and pH in rat heart during ischemia: role of Na+/H+ exchanger. Am J Physiol 276:H1581–H1590

    CAS  PubMed  Google Scholar 

  • Petronilli V, Szabo I, Zoratti M (1989) The inner mitochondrial membrane contains ion-conducting channels similar to those found in bacteria. FEBS Lett 259:137–143

    Article  CAS  PubMed  Google Scholar 

  • Pike MM, Kitakaze M, Marbán E (1990) 23Na-NMR measurements of intracellular sodium in intact perfused ferret hearts during ischemia and reperfusion. Am J Physiol 259:H1767–H1773

    CAS  PubMed  Google Scholar 

  • Pike MM, Luo CS, Clark MD, Kirk KA, Kitakaze M, Madden MC, Cragoe EJ, Pohost GM (1993) NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na(+)-H+ exchange. Am J Physiol 265:H2017–H2026

    CAS  PubMed  Google Scholar 

  • Poburko D, Santo-Domingo J, Demaurex N (2011) Dynamic regulation of the mitochondrial proton gradient during cytosolic calcium elevations. J Biol Chem 286:11672–11684. doi:10.1074/jbc.M110.159962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raaflaub J (1953) Swelling of isolated mitochondria of the liver and their susceptibility to physicochemical influences. Helv Physiol Pharmacol Acta 11:142–156

    CAS  PubMed  Google Scholar 

  • Rezkalla SH, Kloner RA (2004) Ischemic preconditioning and preinfarction angina in the clinical arena. Nat Clin Pract Cardiovasc Med 1:96–102. doi:10.1038/ncpcardio0047

    Article  PubMed  Google Scholar 

  • Ripoll C, Lederer WJ, Nichols CG (1990) Modulation of ATP-sensitive K+ channel activity and contractile behavior in mammalian ventricle by the potassium channel openers cromakalim and RP49356. J Pharmacol Exp Ther 255:429–435

    CAS  PubMed  Google Scholar 

  • Sayen JJ, Sheldon WF, Peirce G, Kuo PT (1958) Polarographic oxygen, the epicardial electrocardiogram and muscle contraction in experimental acute regional ischemia of the left ventricle. Circ Res 6:779–798

    Article  CAS  PubMed  Google Scholar 

  • Scheuer J (1972) The effect of hypoxia on glycolytic ATP production. J Mol Cell Cardiol 4:689–692

    Article  CAS  PubMed  Google Scholar 

  • Scheuer J, Stezoski SW (1970) Protective role of increased myocardial glycogen stores in cardiac anoxia in the rat. Circ Res 27:835–849

    Article  CAS  PubMed  Google Scholar 

  • Seelye RN (1980) Proton generation and control during anaerobic glycolysis in heart cells. J Mol Cell Cardiol 12:1483–1486

    Article  CAS  PubMed  Google Scholar 

  • Shivkumar K, Deutsch NA, Lamp ST, Khuu K, Goldhaber JI, Weiss JN (1997) Mechanism of hypoxic K loss in rabbit ventricle. J Clin Invest 100:1782–1788. doi:10.1172/JCI119705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siemen D, Loupatatzis C, Borecky J, Gulbins E, Lang F (1999) Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line. Biochem Biophys Res Commun 257:549–554. doi:10.1006/bbrc.1999.0496

    Article  CAS  PubMed  Google Scholar 

  • Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483. doi:10.1007/s00395-009-0040-4

    Article  PubMed  Google Scholar 

  • Snowdowne KW, Ertel RJ, Borle AB (1985) Measurement of cytosolic calcium with aequorin in dispersed rat ventricular cells. J Mol Cell Cardiol 17:233–241

    Article  CAS  PubMed  Google Scholar 

  • Steenbergen C, Deleeuw G, Rich T, Williamson JR (1977) Effects of acidosis and ischemia on contractility and intracellular pH of rat heart. Circ Res 41:849–858

    Article  CAS  PubMed  Google Scholar 

  • Steenbergen C, Murphy E, Levy L, London RE (1987) Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ Res 60:700–707

    Article  CAS  PubMed  Google Scholar 

  • Steenbergen C, Murphy E, Watts JA, London RE (1990) Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res 66:135–146

    Article  CAS  PubMed  Google Scholar 

  • Steenbergen C, Perlman ME, London RE, Murphy E (1993) Mechanism of preconditioning. Ionic alterations. Circ Res 72:112–125

    Article  CAS  PubMed  Google Scholar 

  • Stern MD, Silverman HS, Houser SR, Josephson RA, Capogrossi MC, Nichols CG, Lederer WJ, Lakatta EG (1988) Anoxic contractile failure in rat heart myocytes is caused by failure of intracellular calcium release due to alteration of the action potential. Proc Natl Acad Sci U S A 85:6954–6958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo I, Zoratti M (1991) The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 266:3376–3379

    CAS  PubMed  Google Scholar 

  • Szabo I, Zoratti M (1992) The mitochondrial megachannel is the permeability transition pore. J Bioenerg Biomembr 24:111–117

    Article  CAS  PubMed  Google Scholar 

  • ten Hove M, Jansen MA, Nederhoff MGJ, Van Echteld CJA (2007) Combined blockade of the Na+ channel and the Na+/H+ exchanger virtually prevents ischemic Na+ overload in rat hearts. Mol Cell Biochem 297:101–110. doi:10.1007/s11010-006-9334-0

    Article  PubMed  CAS  Google Scholar 

  • Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca(2+) activation of heart mitochondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase. Am J Physiol Cell Physiol 278:C423–C435

    CAS  PubMed  Google Scholar 

  • Toda T, Kadono T, Hoshiai M, Eguchi Y, Nakazawa S, Nakazawa H, Higashijima N, Ishida H (2007) Na+/H+ exchanger inhibitor cariporide attenuates the mitochondrial Ca2+ overload and PTP opening. Am J Physiol Heart Circ Physiol 293:H3517–H3523. doi:10.1152/ajpheart.00483.2006

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Meyer JW, Ashraf M, Shull GE (2003) Mice with a null mutation in the NHE1 Na+-H+ exchanger are resistant to cardiac ischemia-reperfusion injury. Circ Res 93:776–782. doi:10.1161/01.RES.0000094746.24774.DC

    Article  CAS  PubMed  Google Scholar 

  • Weiss J, Couper GS, Hiltbrand B, Shine KI (1984) Role of acidosis in early contractile dysfunction during ischemia: evidence from pHo measurements. Am J Physiol 247:H760–H767

    CAS  PubMed  Google Scholar 

  • Weiss JN, Lamp ST, Shine KI (1989) Cellular K+ loss and anion efflux during myocardial ischemia and metabolic inhibition. Am J Physiol 256:H1165–H1175

    CAS  PubMed  Google Scholar 

  • Williams IA, Xiao X-H, Ju Y-K, Allen DG (2007) The rise of [Na(+)] (i) during ischemia and reperfusion in the rat heart-underlying mechanisms. Pflugers Arch 454:903–912. doi:10.1007/s00424-007-0241-3

    Article  CAS  PubMed  Google Scholar 

  • Williams GSB, Boyman L, Chikando AC, Khairallah RJ, Lederer WJ (2013) Mitochondrial calcium uptake. Proc Natl Acad Sci U S A 110:10479–10486. doi:10.1073/pnas.1300410110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams GSB, Boyman L, Lederer WJ (2015) Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol 78:35–45. doi:10.1016/j.yjmcc.2014.10.019

    Google Scholar 

  • Williamson JR (1966) Glycolytic control mechanisms II. Kinetics of intermediate changes during the aerobic-anoxic transition in perfused rat heart. J Biol Chem 241:5026–5036

    CAS  PubMed  Google Scholar 

  • Wollenberger A, Krause EG (1968) Metabolic control characteristics of the acutely ischemic myocardium. Am J Cardiol 22:349–359

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, O’Rourke B (2002) Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane. Science 298:1029–1033. doi:10.1126/science.1074360

    Article  CAS  PubMed  Google Scholar 

  • Yan GX, Kléber AG (1992) Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle. Circ Res 71:460–470

    Article  CAS  PubMed  Google Scholar 

  • Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151. doi:10.1152/physrev.00009.2003

    Article  CAS  PubMed  Google Scholar 

  • Ylitalo KV, Ala-Rämi A, Liimatta EV, Peuhkurinen KJ, Hassinen IE (2000) Intracellular free calcium and mitochondrial membrane potential in ischemia/reperfusion and preconditioning. J Mol Cell Cardiol 32:1223–1238. doi:10.1006/jmcc.2000.1157

    Article  CAS  PubMed  Google Scholar 

  • Yoshida T, Watanabe M, Engelman DT, Engelman RM, Schley JA, Maulik N, Ho YS, Oberley TD, Das DK (1996) Transgenic mice overexpressing glutathione peroxidase are resistant to myocardial ischemia reperfusion injury. J Mol Cell Cardiol 28:1759–1767. doi:10.1006/jmcc.1996.0165

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Shang W, Zhang X, Gu J, Wang X, Zheng M, Wang Y, Zhou Z, Cao J-M, Ji G, Zhang R, Cheng H (2013) Β-adrenergic-stimulated L-type channel Ca2+ entry mediates hypoxic Ca2+ overload in intact heart. J Mol Cell Cardiol 65:51–58. doi:10.1016/j.yjmcc.2013.09.002

    Article  CAS  PubMed  Google Scholar 

  • Zweier JL, Talukder MAH (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 70:181–190. doi:10.1016/j.cardiores.2006.02.025

    Article  CAS  PubMed  Google Scholar 

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Boyman, L., Williams, G.S.B., Lederer, W.J. (2016). Mitochondrial Calcium and Ischemia: Reperfusion Injury in Heart. In: Hockenbery, D. (eds) Mitochondria and Cell Death. Cell Death in Biology and Diseases. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3612-0_2

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