Mitochondria have emerged as key participants in and regulators of myocardial injury during ischemia and reperfusion. This review examines the sites of damage to cardiac mitochondria during ischemia and focuses on the impact of these defects. The concept that mitochondrial damage during ischemia leads to cardiac injury during reperfusion is addressed. The mechanisms that translate ischemic mitochondrial injury into cellular damage, during both ischemia and early reperfusion, are examined. Next, we discuss strategies that modulate and counteract these mechanisms of mitochondrial-driven injury. The new concept that mitochondria are not merely stochastic sites of oxidative and calcium-mediated injury but that they activate cellular responses of mitochondrial remodeling and cellular reactions that modulate the balance between cell death and recovery is reviewed, and the therapeutic implications of this concept are discussed.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ. 1.  2007. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am. J. Physiol. Cell Physiol. 292:C137–47 [Google Scholar]
  2. Murphy E, Steenbergen C. 2.  2008. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol. Rev. 88:581–609 [Google Scholar]
  3. Yellon DM, Hausenloy DJ. 3.  2007. Myocardial reperfusion injury. N. Engl. J. Med. 357:1121–35 [Google Scholar]
  4. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. 4.  1977. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size versus duration of coronary occlusion in dogs. Circulation 56:786–94 [Google Scholar]
  5. Lesnefsky EJ, Chen Q, Hoppel CL. 5.  2016. Mitochondrial metabolism in aging heart. Circ. Res. 118:1593–611 [Google Scholar]
  6. Halestrap AP, Clarke SJ, Javadov SA. 6.  2004. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc. Res. 61:372–85 [Google Scholar]
  7. Borutaite V, Jekabsone A, Morkuniene R, Brown GC. 7.  2003. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. J. Mol. Cell. Cardiol. 35:357–66 [Google Scholar]
  8. Kubli DA, Gustafsson AB. 8.  2012. Mitochondria and mitophagy: the yin and yang of cell death control. Circ. Res. 111:1208–21 [Google Scholar]
  9. Kung G, Konstantinidis K, Kitsis RN. 9.  2011. Programmed necrosis, not apoptosis, in the heart. Circ. Res. 108:1017–36 [Google Scholar]
  10. Borutaite V, Budriunaite A, Morkuniene R, Brown GC. 10.  2001. Release of mitochondrial cytochrome c and activation of cytosolic caspases induced by myocardial ischaemia. Biochim. Biophys. Acta 1537:101–9 [Google Scholar]
  11. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. 11.  2001. Mitochondrial dysfunction in cardiac disease: ischemia-reperfusion, aging, and heart failure. J. Mol. Cell. Cardiol. 33:1065–89 [Google Scholar]
  12. Palmer JW, Tandler B, Hoppel CL. 12.  1977. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J. Biol. Chem. 252:8731–39 [Google Scholar]
  13. Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL. 13.  1997. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am. J. Physiol. Heart Circ. Physiol. 273:H1544–54 [Google Scholar]
  14. Palmer JW, Tandler B, Hoppel CL. 14.  1986. Heterogeneous response of subsarcolemmal heart mitochondria to calcium. Am. J. Physiol. Heart Circ. Physiol. 250:H741–48 [Google Scholar]
  15. Asemu G, O'Connell KA, Cox JW, Dabkowski ER, Xu W. 15.  et al. 2013. Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion. Am. J. Physiol. Heart Circ. Physiol. 304:H514–28 [Google Scholar]
  16. Pauly DF, Kirk KA, McMillin JB. 16.  1991. Carnitine palmitoyltransferase in cardiac ischemia: a potential site for altered fatty acid metabolism. Circ. Res. 68:1085–94 [Google Scholar]
  17. Lesnefsky EJ, Slabe TJ, Stoll MS, Minkler PE, Hoppel CL. 17.  2001. Myocardial ischemia selectively depletes cardiolipin in rabbit heart subsarcolemmal mitochondria. Am. J. Physiol. Heart Circ. Physiol. 280:H2770–78 [Google Scholar]
  18. Rouslin W. 18.  1983. Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. Am. J. Physiol. Heart Circ. Physiol. 244:H743–48 [Google Scholar]
  19. Lesnefsky EJ, Gudz TI, Migita CT, Ikeda-Saito M, Hassan MO. 19.  et al. 2001. Ischemic injury to mitochondrial electron transport in the aging heart: damage to the iron–sulfur protein subunit of electron transport complex III. Arch. Biochem. Biophys. 385:117–28 [Google Scholar]
  20. Duan J, Karmazyn M. 20.  1989. Relationship between oxidative phosphorylation and adenine nucleotide translocase activity of two populations of cardiac mitochondria and mechanical recovery of ischemic hearts following reperfusion. Can. J. Physiol. Pharmacol. 67:704–9 [Google Scholar]
  21. Kalt MR, Tandler B. 21.  1971. A study of fixation of early amphibian embryos for electron microscopy. J. Ultrastruct. Res. 36:633–45 [Google Scholar]
  22. Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ. 22.  2006. Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J. Pharmacol. Exp. Ther. 319:1405–12 [Google Scholar]
  23. Burwell LS, Nadtochiy SM, Tompkins AJ, Young S, Brookes PS. 23.  2006. Direct evidence for S-nitrosation of mitochondrial complex I. Biochem. J. 394:627–34 [Google Scholar]
  24. Chen R, Fearnley IM, Peak-Chew SY, Walker JE. 24.  2004. The phosphorylation of subunits of complex I from bovine heart mitochondria. J. Biol. Chem. 279:26036–45 [Google Scholar]
  25. Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ. 25.  2008. Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria. Am. J. Physiol. Cell Physiol. 294:C460–66 [Google Scholar]
  26. Ohnishi ST, Ohnishi T, Muranaka S, Fujita H, Kimura H. 26.  et al. 2005. A possible site of superoxide generation in the complex I segment of rat heart mitochondria. J. Bioenerg. Biomembr. 37:1–15 [Google Scholar]
  27. Galkin A, Abramov AY, Frakich N, Duchen MR, Moncada S. 27.  2009. Lack of oxygen deactivates mitochondrial complex I: implications for ischemic injury?. J. Biol. Chem. 284:36055–61 [Google Scholar]
  28. Babot M, Labarbuta P, Birch A, Kee S, Fuszard M. 28.  et al. 2014. ND3, ND1 and 39 kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I. Biochim. Biophys. Acta. 1837:929–39 [Google Scholar]
  29. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY. 29.  et al. 2014. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515:431–35 [Google Scholar]
  30. Pell VR, Chouchani ET, Murphy MP, Brookes PS, Krieg T. 30.  2016. Moving forwards by blocking back-flow: the yin and yang of MI therapy. Circ. Res. 118:898–906 [Google Scholar]
  31. Matsuzaki S, Humphries KM. 31.  2015. Selective inhibition of deactivated mitochondrial complex I by biguanides. Biochemistry 54:2011–21 [Google Scholar]
  32. Lesnefsky EJ, Thompson J, Hu Y, Chen Q. 32.  2016. Administration of metformin during early reperfusion decreases cardiac injury through inhibition of MPTP opening. FASEB J 30:725.4 [Google Scholar]
  33. Chen Q, Ross T, Hu Y, Lesnefsky EJ. 33.  2012. Blockade of electron transport at the onset of reperfusion decreases cardiac injury in aged hearts by protecting the inner mitochondrial membrane. J. Aging Res 2012:753949 [Google Scholar]
  34. Xu A, Szczepanek K, Maceyka MW, Ross T, Bowler E. 34.  et al. 2014. Transient complex I inhibition at the onset of reperfusion by extracellular acidification decreases cardiac injury. Am. J. Physiol. Cell Physiol. 306:C1142–53 [Google Scholar]
  35. Chen Q, Lesnefsky EJ. 35.  2006. Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain. Free Radic. Biol. Med. 40:976–82 [Google Scholar]
  36. Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ. 36.  2003. Production of reactive oxygen species by mitochondria: central role of complex III. J. Biol. Chem. 278:36027–31 [Google Scholar]
  37. Kudin AP, Bimpong-Buta NY, Vielhaber S, Elger CE, Kunz WS. 37.  2004. Characterization of superoxide-producing sites in isolated brain mitochondria. J. Biol. Chem. 279:4127–35 [Google Scholar]
  38. Okun JG, Lummen P, Brandt U. 38.  1999. Three classes of inhibitors share a common binding domain in mitochondrial complex I (NADH:ubiquinone oxidoreductase). J. Biol. Chem. 274:2625–30 [Google Scholar]
  39. Chance B, Williams GR, Hollunger G. 39.  1963. Inhibition of electron and energy transfer in mitochondria. I. Effects of Amytal, thiopental, rotenone, progesterone, and methylene glycol. J. Biol. Chem. 238:418–31 [Google Scholar]
  40. Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR. 40.  et al. 2013. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat. Med. 19:753–59 [Google Scholar]
  41. Ross T, Szczepanek K, Bowler E, Hu Y, Larner A. 41.  et al. 2013. Reverse electron flow-mediated ROS generation in ischemia-damaged mitochondria: role of complex I inhibition versus depolarization of inner mitochondrial membrane. Biochim. Biophys. Acta. 1830:4537–42 [Google Scholar]
  42. Snyder CH, Gutierrez-Cirlos EB, Trumpower BL. 42.  2000. Evidence for a concerted mechanism of ubiquinol oxidation by the cytochrome bc1 complex. J. Biol. Chem. 275:13535–41 [Google Scholar]
  43. Orr AL, Ashok D, Sarantos MR, Shi T, Hughes RE, Brand MD. 43.  2013. Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening. Free Radic. Biol. Med. 65:1047–59 [Google Scholar]
  44. Van Remmen H, Richardson A. 44.  2001. Oxidative damage to mitochondria and aging. Exp. Gerontol. 36:957–68 [Google Scholar]
  45. Covian R, Trumpower BL. 45.  2006. Regulatory interactions between ubiquinol oxidation and ubiquinone reduction sites in the dimeric cytochrome bc1 complex. J. Biol. Chem. 281:30925–32 [Google Scholar]
  46. Moghaddas S, Hoppel CL, Lesnefsky EJ. 46.  2003. Aging defect at the QO site of complex III augments oxyradical production in rat heart interfibrillar mitochondria. Arch. Biochem. Biophys. 414:59–66 [Google Scholar]
  47. Babcock GT, Varotsis C. 47.  1993. Discrete steps in dioxygen activation—the cytochrome oxidase/O2 reaction. J. Bioenerg. Biomembr. 25:71–80 [Google Scholar]
  48. Anthony G, Reimann A, Kadenbach B. 48.  1993. Tissue-specific regulation of bovine heart cytochrome-c oxidase activity by ADP via interaction with subunit VIa. PNAS 90:1652–56 [Google Scholar]
  49. Rosca MG, Vazquez EJ, Kerner J, Parland W, Chandler MP. 49.  et al. 2008. Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. Cardiovasc. Res. 80:30–39 [Google Scholar]
  50. Edoute Y, van der Merwe E, Sanan D, Kotzé JCN, Steinmann C, Lochner A. 50.  1983. Normothermic ischemic cardiac arrest of the isolated working rat heart: effects of time and reperfusion on myocardial ultrastructure, mitochondrial oxidative function, and mechanical recovery. Circ. Res. 53:663–78 [Google Scholar]
  51. Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Serena D, Ruggiero FM. 51.  1999. Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radic. Biol. Med. 27:42–50 [Google Scholar]
  52. Vasdev SC, Biro GP, Narbaitz R, Kako KJ. 52.  1980. Membrane changes induced by early myocardial ischemia in the dog. Can. J. Biochem. 58:1112–19 [Google Scholar]
  53. Kajiyama K, Pauly DF, Hughes H, Yoon SB, Entman ML, McMillin-Wood JB. 53.  1987. Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium. Circ. Res. 61:301–10 [Google Scholar]
  54. Abramovitch DA, Marsh D, Powell GL. 54.  1990. Activation of beef-heart cytochrome c oxidase by cardio-lipin and analogues of cardiolipin. Biochim. Biophys. Acta 1020:34–42 [Google Scholar]
  55. O'Brien PJ. 55.  1969. Intracellular mechanisms for the decomposition of a lipid peroxide. I. Decomposition of a lipid peroxide by metal ions, heme compounds, and nucleophiles. Can. J. Biochem. 47:485–92 [Google Scholar]
  56. Parinandi NL, Zwizinski CW, Schmid HH. 56.  1991. Free radical-induced alterations of myocardial membrane proteins. Arch. Biochem. Biophys. 289:118–23 [Google Scholar]
  57. Pasdois P, Beauvoit B, Tariosse L, Vinassa B, Bonoron-Adèle S, Santos PD. 57.  2006. MitoKATP-dependent changes in mitochondrial volume and in complex II activity during ischemic and pharmacological preconditioning of Langendorff-perfused rat heart. J. Bioenerg. Biomembr. 38:101–12 [Google Scholar]
  58. Chen YR, Chen CL, Pfeiffer DR, Zweier JL. 58.  2007. Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation. J. Biol. Chem. 282:32640–54 [Google Scholar]
  59. Chen CL, Chen J, Rawale S, Varadharaj S, Kaumaya PP. 59.  et al. 2008. Protein tyrosine nitration of the flavin subunit is associated with oxidative modification of mitochondrial complex II in the post-ischemic myocardium. J. Biol. Chem. 283:27991–8003 [Google Scholar]
  60. Wojtovich AP, Brookes PS. 60.  2009. The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial KATP channels. Basic Res. Cardiol. 104:121–29 [Google Scholar]
  61. Drose S, Bleier L, Brandt U. 61.  2011. A common mechanism links differently acting complex II inhibitors to cardioprotection: modulation of mitochondrial reactive oxygen species production. Mol. Pharmacol. 79:814–22 [Google Scholar]
  62. Chen YR, Zweier JL. 62.  2014. Cardiac mitochondria and reactive oxygen species generation. Circ. Res. 114:524–37 [Google Scholar]
  63. Brand MD, Esteves TC. 63.  2005. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2:85–93 [Google Scholar]
  64. Chen Q, Paillard M, Gomez L, Li H, Hu Y, Lesnefsky EJ. 64.  2012. Postconditioning modulates ischemia-damaged mitochondria during reperfusion. J. Cardiovasc. Pharmacol. 59:101–8 [Google Scholar]
  65. Ockaili RA, Bhargava P, Kukreja RC. 65.  2001. Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial KATP channel. Am. J. Physiol. Heart Circ. Physiol. 280:H2406–11 [Google Scholar]
  66. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. 66.  2015. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347:1253–56 [Google Scholar]
  67. Minners J, van den Bos EJ, Yellon DM, Schwalb H, Opie LH, Sack MN. 67.  2000. Dinitrophenol, cyclosporin A, and trimetazidine modulate preconditioning in the isolated rat heart: support for a mitochondrial role in cardioprotection. Cardiovasc. Res. 47:68–73 [Google Scholar]
  68. Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. 68.  2002. Cytochrome c release from mitochondria proceeds by a two-step process. PNAS 99:1259–63 [Google Scholar]
  69. Champattanachai V, Marchase RB, Chatham JC. 69.  2008. Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein O-GlcNAc and increased mitochondrial Bcl-2. Am. J. Physiol. Cell Physiol. 292:C178–87 [Google Scholar]
  70. Lesnefsky EJ, Chen Q, Moghaddas S, Hassan MO, Tandler B, Hoppel CL. 70.  2004. Blockade of electron transport during ischemia protects cardiac mitochondria. J. Biol. Chem. 279:47961–67 [Google Scholar]
  71. Chen Q, Hoppel CL, Lesnefsky EJ. 71.  2006. Blockade of electron transport before cardiac ischemia with the reversible inhibitor amobarbital protects rat heart mitochondria. J. Pharmacol. Exp. Ther. 316:200–7 [Google Scholar]
  72. Ilangovan G, Liebgott T, Kutala VK, Petryakov S, Zweier JL, Kuppusamy P. 72.  2004. EPR oximetry in the beating heart: myocardial oxygen consumption rate as an index of postischemic recovery. Magn. Reson. Med. 51:835–42 [Google Scholar]
  73. Aldakkak M, Stowe DF, Chen Q, Lesnefsky EJ, Camara AK. 73.  2008. Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release. Cardiovasc. Res. 77:406–15 [Google Scholar]
  74. Chandel NS, Budinger GR, Schumacker PT. 74.  1996. Molecular oxygen modulates cytochrome c oxidase function. J. Biol. Chem. 271:18672–77 [Google Scholar]
  75. Vanden Hoek TL, Li C, Shao Z, Schumacker PT, Becker LB. 75.  1997. Significant levels of oxidants are generated by isolated cardiomyocytes during ischemia prior to reperfusion. J. Mol. Cell. Cardiol. 29:2571–83 [Google Scholar]
  76. Kelso GF, Porteous CM, Hughes G, Ledgerwood EC, Gane AM. 76.  et al. 2002. Prevention of mitochondrial oxidative damage using targeted antioxidants. Ann. N. Y. Acad. Sci. 959:263–74 [Google Scholar]
  77. Dongworth RK, Hall AR, Burke N, Hausenloy DJ. 77.  2014. Targeting mitochondria for cardioprotection: examining the benefit for patients. Future Cardiol 10:255–72 [Google Scholar]
  78. Becker LB, Vanden Hoek TL, Shao ZH, Li CQ, Schumacker PT. 78.  1999. Generation of superoxide in cardiomyocytes during ischemia before reperfusion. Am. J. Physiol. Heart Circ. Physiol. 277:H2240–46 [Google Scholar]
  79. Pinakoulaki E, Pfitzner U, Ludwig B, Varotsis C. 79.  2003. Direct detection of Fe(IV)=O intermediates in the cytochrome aa3 oxidase from Paracoccus denitrificans/H2O2 reaction. J. Biol. Chem. 278:18761–66 [Google Scholar]
  80. Castello PR, David PS, McClure T, Crook Z, Poyton RO. 80.  2006. Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab 3:277–87 [Google Scholar]
  81. Chen Q, Yin G, Stewart S, Hu Y, Lesnefsky EJ. 81.  2010. Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemia. Biochem. Biophys. Res. Commun. 397:656–60 [Google Scholar]
  82. Sparagna GC, Lesnefsky EJ. 82.  2009. Cardiolipin remodeling in the heart. J. Cardiovasc. Pharmacol. 53:290–301 [Google Scholar]
  83. Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB. 83.  et al. 2005. Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat. Chem. Biol. 1:223–32 [Google Scholar]
  84. Vladimirov YA, Proskurnina EV, Izmailov DY, Novikov AA, Brusnichkin AV. 84.  et al. 2006. Cardiolipin activates cytochrome c peroxidase activity since it facilitates H2O2 access to heme. Biochem. (Mosc.) 71:998–1005 [Google Scholar]
  85. Aluri HS, Simpson DC, Allegood JC, Hu Y, Szczepanek K. 85.  et al. 2014. Electron flow into cytochrome c coupled with reactive oxygen species from the electron transport chain converts cytochrome c to a cardiolipin peroxidase: role during ischemia-reperfusion. Biochim. Biophys. Acta 1840:3199–207 [Google Scholar]
  86. Birk AV, Liu S, Soong Y, Mills W, Singh P. 86.  et al. 2013. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J. Am. Soc. Nephrol. 24:1250–61 [Google Scholar]
  87. Kloner RA, Hale SL, Dai W, Gorman RC, Shuto T. 87.  et al. 2012. Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective peptide. J. Am. Heart Assoc. 1:e001644 [Google Scholar]
  88. Gibson CM, Giugliano RP, Kloner RA, Bode C, Tendera M. 88.  et al. 2016. EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur. Heart J. 37:1296–303 [Google Scholar]
  89. Orsini F, Moroni M, Contursi C, Yano M, Pelicci P. 89.  et al. 2006. Regulatory effects of the mitochondrial energetic status on mitochondrial p66Shc. Biol. Chem. 387:1405–10 [Google Scholar]
  90. Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M. 90.  et al. 2005. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122:221–33 [Google Scholar]
  91. Yang M, Stowe DF, Udoh KB, Heisner JS, Camara AK. 91.  2014. Reversible blockade of complex I or inhibition of PKCβ reduces activation and mitochondria translocation of p66Shc to preserve cardiac function after ischemia. PLOS ONE 9:e113534 [Google Scholar]
  92. Lesnefsky EJ, Chen Q, Slabe TJ, Stoll MS, Minkler PE. 92.  et al. 2004. Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin. Am. J. Physiol. Heart Circ. Physiol. 287:H258–67 [Google Scholar]
  93. Ambrosio G, Zweier JL, Duilio C, Kuppusamy P, Santoro G. 93.  et al. 1993. Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. J. Biol. Chem. 268:18532–41 [Google Scholar]
  94. Han D, Antunes F, Canali R, Rettori D, Cadenas E. 94.  2003. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 278:5557–63 [Google Scholar]
  95. Chen Q, Lesnefsky EJ. 95.  2011. Blockade of electron transport during ischemia preserves bcl-2 and inhibits opening of the mitochondrial permeability transition pore. FEBS Lett 585:921–26 [Google Scholar]
  96. Tanaka-Esposito C, Chen Q, Lesnefsky EJ. 96.  2012. Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts. Transl. Res. 160:207–16 [Google Scholar]
  97. Aldakkak M, Camara AK, Heisner JS, Yang M, Stowe DF. 97.  2011. Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts. Pharmacol. Res. 64:381–92 [Google Scholar]
  98. Brown GC, Borutaite V. 98.  2007. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc. Res. 75:283–90 [Google Scholar]
  99. Nadtochiy SM, Burwell LS, Brookes PS. 99.  2007. Cardioprotection and mitochondrial S-nitrosation: effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia-reperfusion injury. J. Mol. Cell. Cardiol 42:812–25 [Google Scholar]
  100. Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA. 100.  et al. 2007. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J. Exp. Med. 204:2089–102 [Google Scholar]
  101. Xu A, Szczepanek K, Hu Y, Lesnefsky EJ, Chen Q. 101.  2013. Cardioprotection by modulation of mitochondrial respiration during ischemia-reperfusion: role of apoptosis-inducing factor. Biochem. Biophys. Res. Commun. 435:627–33 [Google Scholar]
  102. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H. 102.  et al. 2005. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–62 [Google Scholar]
  103. Halestrap AP. 103.  2009. What is the mitochondrial permeability transition pore?. J. Mol. Cell. Cardiol. 46:821–31 [Google Scholar]
  104. Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F. 104.  et al. 2013. Dimers of mitochondrial ATP synthase form the permeability transition pore. PNAS 110:5887–92 [Google Scholar]
  105. Sammut IA, Burton K, Balogun E, Sarathchandra P, Brooks KJ. 105.  et al. 2000. Time-dependent impairment of mitochondrial function after storage and transplantation of rabbit kidneys. Transplantation 69:1265–75 [Google Scholar]
  106. Gateau-Roesch O, Argaud L, Ovize M. 106.  2006. Mitochondrial permeability transition pore and postconditioning. Cardiovasc. Res. 70:264–73 [Google Scholar]
  107. Crompton M. 107.  1999. The mitochondrial permeability transition pore and its role in cell death. Biochem. J. 341:233–49 [Google Scholar]
  108. Cao CM, Yan WY, Liu J, Kam KW, Zhan SZ. 108.  et al. 2006. Attenuation of mitochondrial, but not cytosolic, Ca2+ overload reduces myocardial injury induced by ischemia and reperfusion. Acta Pharmacol. Sin. 27:911–18 [Google Scholar]
  109. Amberger A, Weiss H, Haller T, Kock G, Hermann M. 109.  et al. 2001. A subpopulation of mitochondria prevents cytosolic calcium overload in endothelial cells after cold ischemia/reperfusion. Transplantation 71:1821–27 [Google Scholar]
  110. An J, Varadarajan SG, Camara A, Chen Q, Novalija E. 110.  et al. 2001. Blocking Na+/H+ exchange reduces [Na+]i and [Ca2+]i load after ischemia and improves function in intact hearts. Am. J. Physiol. Heart Circ. Physiol. 281:H2398–409 [Google Scholar]
  111. An J, Rhodes SS, Jiang MT, Bosnjak ZJ, Tian M, Stowe DF. 111.  2006. Anesthetic preconditioning enhances Ca2+ handling and mechanical and metabolic function elicited by Na+-Ca2+ exchange inhibition in isolated hearts. Anesthesiology 105:541–49 [Google Scholar]
  112. Halestrap AP, Connern CP, Griffiths EJ, Kerr PM. 112.  1997. Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol. Cell. Biochem. 174:167–72 [Google Scholar]
  113. Piot C, Croisille P, Staat P, Thibault H, Rioufol G. 113.  et al. 2008. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N. Engl. J. Med. 359:473–81 [Google Scholar]
  114. Stewart S, Lesnefsky EJ, Chen Q. 114.  2009. Reversible blockade of electron transport with amobarbital at the onset of reperfusion attenuates cardiac injury. Transl. Res. 153:224–31 [Google Scholar]
  115. Paillard M, Gomez L, Augeul L, Loufouat J, Lesnefsky EJ, Ovize M. 115.  2009. Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential. J. Mol. Cell. Cardiol. 46:902–9 [Google Scholar]
  116. Chen Q, Paillard M, Gomez L, Ross T, Hu Y. 116.  et al. 2011. Activation of mitochondrial μ-calpain increases AIF cleavage in cardiac mitochondria during ischemia–reperfusion. Biochem. Biophys. Res. Commun. 415:533–38 [Google Scholar]
  117. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ. 117.  et al. 2002. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–63 [Google Scholar]
  118. Szczepanek K, Lesnefsky EJ, Larner AC. 118.  2012. Multi-tasking: nuclear transcription factors with novel roles in the mitochondria. Trends Cell Biol 22:429–37 [Google Scholar]
  119. Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI. 119.  et al. 2001. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 104:979–81 [Google Scholar]
  120. Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R. 120.  2008. The myocardial JAK/STAT pathway: from protection to failure. Pharmacol. Ther. 120:172–85 [Google Scholar]
  121. Szczepanek K, Chen Q, Derecka M, Salloum FN, Zhang Q. 121.  et al. 2011. Mitochondrial-targeted signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species. J. Biol. Chem. 286:29610–20 [Google Scholar]
  122. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R. 122.  2010. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res. Cardiol. 105:771–85 [Google Scholar]
  123. Wegrzyn J, Potla R, Chwae YJ, Sepuri NBV, Zhang Q. 123.  et al. 2009. Function of mitochondrial Stat3 in cellular respiration. Science 323:793–97 [Google Scholar]
  124. Heusch G, Musiolik J, Gedik N, Skyschally A. 124.  2011. Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ. Res. 109:1302–8 [Google Scholar]
  125. Szczepanek K, Xu A, Hu Y, Thompson J, He J. 125.  et al. 2015. Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury. Basic Res. Cardiol. 110:53 [Google Scholar]
  126. Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG. 126.  et al. 2010. Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am. J. Physiol. Heart Circ. Physiol. 299:H1265–70 [Google Scholar]
  127. Beigel F, Friedrich M, Probst C, Sotlar K, Göke B. 127.  et al. 2014. Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members. PLOS ONE 9:e93498 [Google Scholar]
  128. Lecour S, Suleman N, Deuchar GA, Somers S, Lacerda L. 128.  et al. 2005. Pharmacological preconditioning with tumor necrosis factor-α activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal–regulated kinase). Circulation 112:3911–18 [Google Scholar]
  129. Bolli R. 129.  2007. Preconditioning: a paradigm shift in the biology of myocardial ischemia. Am. J. Physiol. Heart Circ. Physiol. 292:H19–27 [Google Scholar]
  130. Minamino T. 130.  2012. Cardioprotection from ischemia/reperfusion injury: basic and translational research. Circ. J. 76:1074–82 [Google Scholar]
  131. Miura T, Tanno M. 131.  2012. The mPTP and its regulatory proteins: final common targets of signalling pathways for protection against necrosis. Cardiovasc. Res. 94:181–89 [Google Scholar]
  132. Peart JN, Headrick JP. 132.  2009. Clinical cardioprotection and the value of conditioning responses. Am. J. Physiol. Heart Circ. Physiol. 296:H1705–20 [Google Scholar]
  133. Yang X, Cohen MV, Downey JM. 133.  2010. Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc. Drugs Ther. 24:225–34 [Google Scholar]
  134. Varadarajan SG, An J, Novalija E, Stowe DF. 134.  2002. Sevoflurane before or after ischemia improves contractile and metabolic function while reducing myoplasmic Ca2+ loading in intact hearts. Anesthesiology 96:125–33 [Google Scholar]
  135. Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W. 135.  2005. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth. Analg. 101:1252–60 [Google Scholar]
  136. Coetzee WA. 136.  2013. Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol. Ther. 140:167–75 [Google Scholar]
  137. Lesnefsky EJ. 137.  2002. The IONA study: preparing the myocardium for ischaemia?. Lancet 359:1262–63 [Google Scholar]
  138. Heusch G. 138.  2013. Remote conditioning: the future of cardioprotection?. J. Cardiovasc. Med. 14:176–79 [Google Scholar]
  139. Heusch G. 139.  2015. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ. Res. 116:674–99 [Google Scholar]
  140. Li J, Rohailla S, Gelber N, Rutka J, Sabah N. 140.  et al. 2014. MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res. Cardiol. 109:423 [Google Scholar]
  141. Basalay M, Barsukevich V, Mastitskaya S, Mrochek A, Pernow J. 141.  et al. 2012. Remote ischaemic pre- and delayed postconditioning – similar degree of cardioprotection but distinct mechanisms. Exp. Physiol. 97:908–17 [Google Scholar]
  142. Zhu SB, Liu Y, Zhu Y, Yin GL, Wang RP. 142.  et al. 2013. Remote preconditioning, perconditioning, and postconditioning: a comparative study of their cardio-protective properties in rat models. Clinics 68:263–68 [Google Scholar]
  143. Andreka G, Vertesaljai M, Szantho G, Font G, Piroth Z. 143.  et al. 2007. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. Heart 93:749–52 [Google Scholar]
  144. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. 144.  2008. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J. Surg. Res. 150:304–30 [Google Scholar]
  145. Vinten-Johansen J, Shi W. 145.  2013. The science and clinical translation of remote postconditioning. J. Cardiovasc. Med. 14:206–13 [Google Scholar]
  146. Przyklenk K, Whittaker P. 146.  2013. Genesis of remote conditioning: action at a distance – ‘hypotheses non fingo’?. J. Cardiovasc. Med. 14:180–86 [Google Scholar]
  147. Mastitskaya S, Marina N, Gourine A, Gilbey MP, Spyer KM. 147.  et al. 2012. Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones. Cardiovasc. Res. 95:487–94 [Google Scholar]
  148. Lim SY, Yellon DM, Hausenloy DJ. 148.  2010. The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res. Cardiol. 105:651–55 [Google Scholar]
  149. Pickard JM, Davidson SM, Hausenloy DJ, Yellon DM. 149.  2016. Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning. Basic Res. Cardiol. 111:50 [Google Scholar]
  150. Mastitskaya S, Basalay M, Hosford PS, Ramage AG, Gourine A, Gourine AV. 150.  2016. Identifying the source of a humoral factor of remote (pre)conditioning cardioprotection. PLOS ONE 11:e0150108 [Google Scholar]
  151. Wang L, Oka N, Tropak M, Callahan J, Lee J. 151.  et al. 2008. Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J. Thorac. Cardiovasc. Surg. 136:335–42 [Google Scholar]
  152. Rahman IA, Mascaro JG, Steeds RP, Frenneaux MP, Nightingale P. 152.  et al. 2010. Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment?. Circulation 122:S53–59 [Google Scholar]
  153. Karuppasamy P, Chaubey S, Dew T, Musto R, Sherwood R. 153.  et al. 2011. Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation?. Basic Res. Cardiol. 106:511–19 [Google Scholar]
  154. Young PJ, Dalley P, Garden A, Horrocks C, La Flamme A. 154.  et al. 2012. A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol. Basic Res. Cardiol. 107:256 [Google Scholar]
  155. Hausenloy DJ, Candilio L, Laing C, Kunst G, Pepper J. 155.  et al. 2011. Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-centre randomized double-blinded controlled clinical trial. Clin. Res. Cardiol. 101:339–48 [Google Scholar]
  156. Meybohm P, Zacharowski K, Cremer J, Roesner J, Kletzin F. 156.  et al. 2012. Remote ischaemic preconditioning for heart surgery. The study design for a multi-center randomized double-blinded controlled clinical trial—the RIPHeart-Study. Eur. Heart J. 33:1423–26 [Google Scholar]
  157. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK. 157.  et al. 2010. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–34 [Google Scholar]
  158. Rentoukas I, Giannopoulos G, Kaoukis A, Kossyvakis C, Raisakis K. 158.  et al. 2010. Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc. Interv. 3:49–55 [Google Scholar]
  159. Goll DE, Thompson VF, Li H, Wei W, Cong J. 159.  2003. The calpain system. Physiol. Rev. 83:731–801 [Google Scholar]
  160. Thompson VF, Lawson K, Goll DE. 160.  2000. Effect of μ-calpain on m-calpain. Biochem. Biophys. Res. Commun. 267:495–99 [Google Scholar]
  161. Vosler PS, Brennan CS, Chen J. 161.  2008. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol. Neurobiol. 38:78–100 [Google Scholar]
  162. Ozaki T, Tomita H, Tamai M, Ishiguro S. 162.  2007. Characteristics of mitochondrial calpains. J. Biochem. 142:365–76 [Google Scholar]
  163. Joshi A, Bondada V, Geddes JW. 163.  2009. Mitochondrial μ-calpain is not involved in the processing of apoptosis-inducing factor. Exp. Neurol. 218:221–27 [Google Scholar]
  164. Arrington DD, Van Vleet TR, Schnellmann RG. 164.  2006. Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. Am. J. Physiol. Cell Physiol. 291:C1159–71 [Google Scholar]
  165. Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA. 165.  2001. Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J. Biol. Chem. 276:30724–28 [Google Scholar]
  166. Randriamboavonjy V, Pistrosch F, Bolck B, Schwinger RH, Dixit M. 166.  et al. 2008. Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and μ-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Circulation 117:52–60 [Google Scholar]
  167. Ong SB, Hall AR, Hausenloy DJ. 167.  2013. Mitochondrial dynamics in cardiovascular health and disease. Antioxid. Redox Signal. 19:400–14 [Google Scholar]
  168. Marin-Garcia J, Akhmedov AT, Moe GW. 168.  2013. Mitochondria in heart failure: the emerging role of mitochondrial dynamics. Heart Fail. Rev. 18:439–56 [Google Scholar]
  169. Vásquez-Trincado C, García-Carvajal I, Pennanen C, Parra V, Hill JA. 169.  et al. 2016. Mitochondrial dynamics, mitophagy and cardiovascular disease. J. Physiol. 594:509–25 [Google Scholar]
  170. de Brito OM, Scorrano L. 170.  2009. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: the role of Ras. Mitochondrion 9:222–26 [Google Scholar]
  171. Piquereau J, Caffin F, Novotova M, Lemaire C, Veksler V. 171.  et al. 2013. Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell?. Front. Physiol. 4:102 [Google Scholar]
  172. Hwang SJ, Kim W. 172.  2014. Mitochondrial dynamics in the heart as a novel therapeutic target for cardioprotection. Chonnam Med. J 49:101–7 [Google Scholar]
  173. Zepeda R, Kuzmicic J, Parra V, Troncoso R, Pennanen C. 173.  et al. 2014. Drp1 loss-of-function reduces cardiomyocyte oxygen dependence protecting the heart from ischemia-reperfusion injury. J. Cardiovasc. Pharmacol. 63:477–87 [Google Scholar]
  174. Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. 174.  2012. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–22 [Google Scholar]
  175. Pride CK, Mo L, Quesnelle K, Dagda RK, Murillo D. 175.  et al. 2014. Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion. Cardiovasc. Res. 101:57–68 [Google Scholar]
  176. Long B, Wang K, Li N, Murtaza I, Xiao JY. 176.  et al. 2013. miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor. Free Radic. Biol. Med. 65:371–79 [Google Scholar]
  177. Hill JA. 177.  2011. Autophagy in cardiac plasticity and disease. Pediatr. Cardiol. 32:282–89 [Google Scholar]
  178. Youle RJ, van der Bliek AM. 178.  2012. Mitochondrial fission, fusion, and stress. Science 337:1062–65 [Google Scholar]
  179. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H. 179.  et al. 2007. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100:914–22 [Google Scholar]
  180. Narendra DP, Youle RJ. 180.  2011. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid. Redox Signal. 14:1929–38 [Google Scholar]
  181. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K. 181.  et al. 2010. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell. Biol. 189:211–21 [Google Scholar]
  182. Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R. 182.  et al. 2012. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 13:378–85 [Google Scholar]
  183. Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW. 183.  2004. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol. Cell. Biol. 24:8055–68 [Google Scholar]
  184. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA. 184.  et al. 2007. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282:24131–45 [Google Scholar]
  185. Kubli DA, Zhang X, Lee Y, Hanna RA, Quinsay MN. 185.  et al. 2013. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J. Biol. Chem. 288:915–26 [Google Scholar]
  186. Gottlieb RA, Mentzer RM Jr, Linton PJ. 186.  2011. Impaired mitophagy at the heart of injury. Autophagy 7:1573–74 [Google Scholar]
  187. Zhang J, Nadtochiy SM, Urciuoli WR, Brookes PS. 187.  2016. The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy. Am. J. Physiol. Heart Circ. Physiol. 310:H29–38 [Google Scholar]
  188. Chipuk JE, Bouchier-Hayes L, Green DR. 188.  2006. Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396–402 [Google Scholar]
  189. Hausenloy DJ, Yellon DM. 189.  2007. Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail. Rev. 12:217–34 [Google Scholar]
  190. Hausenloy DJ, Yellon DM. 190.  2003. The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J. Mol. Cell. Cardiol. 35:339–41 [Google Scholar]
  191. Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R. 191.  et al. 2011. Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis 2:e244 [Google Scholar]
  192. Ong SG, Hausenloy DJ. 192.  2012. Hypoxia-inducible factor as a therapeutic target for cardioprotection. Pharmacol. Ther. 136:69–81 [Google Scholar]
  193. Wong R, Aponte AM, Steenbergen C, Murphy E. 193.  2010. Cardioprotection leads to novel changes in the mitochondrial proteome. Am. J. Physiol. Heart Circ. Physiol. 298:H75–91 [Google Scholar]
  194. Murphy E, Steenbergen C. 194.  2011. What makes the mitochondria a killer? Can we condition them to be less destructive?. Biochim. Biophys. Acta 1813:1302–8 [Google Scholar]
  195. Gustafsson AB, Gottlieb RA. 195.  2009. Autophagy in ischemic heart disease. Circ. Res. 104:150–58 [Google Scholar]
  196. Dorn GW II, Vega RB, Kelly DP. 196.  2015. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev 29:1981–91 [Google Scholar]
  197. Whitaker RM, Corum D, Beeson CC, Schnellmann RG. 197.  2016. Mitochondrial biogenesis as a pharmacological target: a new approach to acute and chronic diseases. Annu. Rev. Pharmacol. Toxicol. 56:229–49 [Google Scholar]
  198. Lesnefsky EJ, He D, Moghaddas S, Hoppel CL. 198.  2006. Reversal of mitochondrial defects before ischemia protects the aged heart. FASEB J 20:1543–45 [Google Scholar]
  199. Gallogly MM, Shelton MD, Qanungo S, Pai HV, Starke DW. 199.  et al. 2010. Glutaredoxin regulates apoptosis in cardiomyocytes via NFκB targets Bcl-2 and Bcl-xL: implications for cardiac aging. Antioxid. Redox Signal. 12:1339–53 [Google Scholar]
  200. Rousou AJ, Ericsson M, Federman M, Levitsky S, McCully JD. 200.  2004. Opening of mitochondrial KATP channels enhances cardioprotection through the modulation of mitochondrial matrix volume, calcium accumulation, and respiration. Am. J. Physiol. Heart Circ. Physiol. 287:H1967–76 [Google Scholar]
  201. Riess ML, Eells JT, Kevin LG, Camara AK, Henry MM, Stowe DF. 201.  2004. Attenuation of mitochondrial respiration by sevoflurane in isolated cardiac mitochondria is mediated in part by reactive oxygen species. Anesthesiology 100:498–505 [Google Scholar]
  202. Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY. 202.  et al. 2009. Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic. Biol. Med. 46:1439–53 [Google Scholar]
  203. Kagan VE, Borisenko GG, Tyurina YY, Tyurin VA, Jiang J. 203.  et al. 2004. Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine. Free Radic. Biol. Med. 37:1963–85 [Google Scholar]
  204. Kagan VE, Tyurina YY, Bayir H, Chu CT, Kapralov AA. 204.  et al. 2006. The “pro-apoptotic genies” get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexes. Chem. Biol. Interact. 163:15–28 [Google Scholar]
  205. Murry CE, Jennings RB, Reimer KA. 205.  1986. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–36 [Google Scholar]
  206. Thompson J, Hu Y, Lesnefsky EJ, Chen Q. 206.  2015. Activation of mitochondrial calpain and increased cardiac injury: beyond AIF release. Am. J. Physiol. Heart Circ. Physiol. 310:H376–84 [Google Scholar]
  207. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP. 207.  et al. 2003. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 285:H579–88 [Google Scholar]
  208. Penna C, Perrelli MG, Tullio F, Angotti C, Camporeale A. 208.  et al. 2013. Diazoxide postconditioning induces mitochondrial protein S-nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE. Basic Res. Cardiol. 108:371 [Google Scholar]
  209. Luan HF, Zhao ZB, Zhao QH, Zhu P, Xiu MY, Ji Y. 209.  2012. Hydrogen sulfide postconditioning protects isolated rat hearts against ischemia and reperfusion injury mediated by the JAK2/STAT3 survival pathway. Braz. J. Med. Biol. Res 45:898–905 [Google Scholar]
  210. Kelso GF, Porteous CM, Hughes G, Ledgerwood EC, Gane AM. 210.  et al. 2002. Prevention of mitochondrial oxidative damage using targeted antioxidants. Ann. N. Y. Acad. Sci. 959:263–74 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error