Skip to main content
SpringerLink
Log in
Book cover

Mitochondria and Their Role in Cardiovascular Disease pp 313–325Cite as

Role of Mitochondria in Ischemia and Cardioprotection

  • Chapter
  • First Online:

  • 1781 Accesses

Abstract

Ischemia and postischemic reperfusion cause a wide array of functional and structural alterations of mitochondria. Although mitochondrial impairment is recognized as pivotal in determining loss of cell viability, the causal relationships among the various processes involved is not well defined. Nevertheless, there is a consensus in attributing a crucial role to opening of the mitochondrial permeability transition pore (MPTP). Strong support for this concept has recently been provided by the reduced infarct size in mice lacking cyclophilin D. This protein located within the mitochondrial matrix favors MPTP opening by increasing its sensitivity to Ca2+ in a process that is antagonized by cyclosporin A. Genetic approaches have also been used to demonstrate that adenine nucleotide translocase is not an essential component of the MPTP. Key factors linking mitochondrial dysfunction to myocardial injury have been studied along with potential protective mechanisms elicited by endogenous processes and pharmacological treatments. In particular, a reduced rate of ATP hydrolysis and a slight increase in reactive oxygen species (ROS) formation appear to represent the prevailing components of self-defense mechanisms, especially in the case of ischemic preconditioning. These cardioprotective processes are activated by signaling pathways, which converge on mitochondria activating the mitochondrial KATP channels and/or inhibiting the MPTP. These pathways can also be stimulated by pharmacological treatments. Another major goal for cardioprotection is decreasing the burst in mitochondrial ROS formation associated with postischemic reperfusion. Finally, given an inhibition of fatty acid oxidation associated with cardioprotection, mitochondrial targets for therapeutic intervention may include the switch of substrate being utilized.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Adlam VJ, Harrison JC, Porteous CM, et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005;19(9):1088–95.

    PubMed  CAS  Google Scholar 

  2. Burwell LS, Brookes PS. Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury. Antioxid Redox Signal. 2008;10(3):579–99.

    PubMed  CAS  Google Scholar 

  3. Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res. 2004;95(10):957–70.

    PubMed  CAS  Google Scholar 

  4. Di LF, Menabo R, Canton M, Petronilli V. The role of mitochondria in the salvage and the injury of the ischemic myocardium. Biochim Biophys Acta. 1998;1366(1–2):69–78.

    Google Scholar 

  5. O’Rourke B. Pathophysiological and protective roles of mitochondrial ion channels. J Physiol. 2000;529(Pt 1):23–36.

    PubMed  Google Scholar 

  6. Di LF, Canton M, Menabo R, Dodoni G, Bernardi P. Mitochondria and reperfusion injury. The role of permeability transition. Basic Res Cardiol. 2003;98(4):235–41.

    Google Scholar 

  7. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res. 2004;61(3):372–85.

    PubMed  CAS  Google Scholar 

  8. Weiss JN, Korge P, Honda HM, Ping P. Role of the mitochondrial permeability transition in myocardial disease. Circ Res. 2003;93(4):292–301.

    PubMed  CAS  Google Scholar 

  9. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol. 2003;35(4):339–41.

    PubMed  CAS  Google Scholar 

  10. Crompton M, Costi A, Hayat L. Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J. 1987;245(3):915–8.

    PubMed  CAS  Google Scholar 

  11. Crompton M, Costi A. A heart mitochondrial Ca2(+)-dependent pore of possible relevance to re-perfusion-induced injury. Evidence that ADP facilitates pore interconversion between the closed and open states. Biochem J. 1990;266(1):33–9.

    PubMed  CAS  Google Scholar 

  12. Nazareth W, Yafei N, Crompton M. Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol. 1991;23(12):1351–4.

    PubMed  CAS  Google Scholar 

  13. Griffiths EJ, Halestrap AP. Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol. 1993;25(12):1461–9.

    PubMed  CAS  Google Scholar 

  14. Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003;549(Pt 2):513–24.

    PubMed  CAS  Google Scholar 

  15. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation. 2005;111(2):194–7.

    PubMed  CAS  Google Scholar 

  16. Murphy E. Primary and secondary signaling pathways in early preconditioning that converge on the mitochondria to produce cardioprotection. Circ Res. 2004;94(1):7–16.

    PubMed  CAS  Google Scholar 

  17. Pain T, Yang XM, Critz SD, et al. Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res. 2000;87(6):460–6.

    PubMed  CAS  Google Scholar 

  18. Oldenburg O, Cohen MV, Yellon DM, Downey JM. Mitochondrial K(ATP) channels: role in cardioprotection. Cardiovasc Res. 2002;55(3):429–37.

    PubMed  CAS  Google Scholar 

  19. Hausenloy D, Wynne A, Duchen M, Yellon D. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation. 2004;109(14):1714–7.

    PubMed  CAS  Google Scholar 

  20. Di LF, Blank PS, Colonna R, et al. Mitochondrial membrane potential in single living adult rat cardiac myocytes exposed to anoxia or metabolic inhibition. J Physiol. 1995;486(Pt 1):1–13.

    Google Scholar 

  21. Di LF, Bernardi P. Mitochondrial function as a determinant of recovery or death in cell response to injury. Mol Cell Biochem. 1998;184(1–2):379–91.

    Google Scholar 

  22. Murphy E, Steenbergen C. Preconditioning: the mitochondrial connection. Annu Rev Physiol. 2007;69:51–67.

    PubMed  CAS  Google Scholar 

  23. Allen DG, Orchard CH. Myocardial contractile function during ischemia and hypoxia. Circ Res. 1987;60(2):153–68.

    PubMed  CAS  Google Scholar 

  24. Jennings RB, Steenbergen Jr C. Nucleotide metabolism and cellular damage in myocardial ischemia. Annu Rev Physiol. 1985;47:727–49.

    PubMed  CAS  Google Scholar 

  25. Corr PB, Gross RW, Sobel BE. Amphipathic metabolites and membrane dysfunction in ischemic myocardium. Circ Res. 1984;55(2):135–54.

    PubMed  CAS  Google Scholar 

  26. Katz AM, Messineo FC. Lipid-membrane interactions and the pathogenesis of ischemic damage in the myocardium. Circ Res. 1981;48(1):1–16.

    PubMed  CAS  Google Scholar 

  27. Bernardi P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev. 1999;79(4):1127–55.

    PubMed  CAS  Google Scholar 

  28. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120(4):483–95.

    PubMed  CAS  Google Scholar 

  29. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(Pt 2):335–44.

    PubMed  CAS  Google Scholar 

  30. Fridovich I. Mitochondria: are they the seat of senescence? Aging Cell. 2004;3(1):13–6.

    PubMed  CAS  Google Scholar 

  31. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem. 2002;277(47):44784–90.

    PubMed  CAS  Google Scholar 

  32. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112.

    PubMed  CAS  Google Scholar 

  33. Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29(3–4):222–30.

    PubMed  CAS  Google Scholar 

  34. Giorgio M, Migliaccio E, Orsini F, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122(2):221–33.

    PubMed  CAS  Google Scholar 

  35. Orsini F, Migliaccio E, Moroni M, et al. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem. 2004;279(24):25689–95.

    PubMed  CAS  Google Scholar 

  36. Migliaccio E, Giorgio M, Mele S, et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402(6759):309–13.

    PubMed  CAS  Google Scholar 

  37. Pinton P, Rimessi A, Marchi S, et al. Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science. 2007;315(5812):659–63.

    PubMed  CAS  Google Scholar 

  38. Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta. 1995;1241(2):139–76.

    PubMed  Google Scholar 

  39. Soriano ME, Nicolosi L, Bernardi P. Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor-alpha. J Biol Chem. 2004;279(35):36803–8.

    PubMed  CAS  Google Scholar 

  40. Petronilli V, Nicolli A, Costantini P, Colonna R, Bernardi P. Regulation of the permeability transition pore, a voltage-dependent mitochondrial channel inhibited by cyclosporin A. Biochim Biophys Acta. 1994;1187(2):255–9.

    PubMed  CAS  Google Scholar 

  41. Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem. 2004;73:87–106.

    PubMed  CAS  Google Scholar 

  42. Bernardi P, Azzone GF. Cytochrome c as an electron shuttle between the outer and inner mitochondrial membranes. J Biol Chem. 1981;256(14):7187–92.

    PubMed  CAS  Google Scholar 

  43. Scorrano L, Ashiya M, Buttle K, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell. 2002;2(1):55–67.

    PubMed  CAS  Google Scholar 

  44. Ichas F, Jouaville LS, Mazat JP. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell. 1997;89(7):1145–53.

    PubMed  CAS  Google Scholar 

  45. Hunter DR, Haworth RA. The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch Biochem Biophys. 1979;195(2):468–77.

    PubMed  CAS  Google Scholar 

  46. Altschuld RA, Hohl CM, Castillo LC, Garleb AA, Starling RC, Brierley GP. Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am J Physiol. 1992;262(6 Pt 2):H1699–704.

    PubMed  CAS  Google Scholar 

  47. Jouaville LS, Ichas F, Holmuhamedov EL, Camacho P, Lechleiter JD. Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature. 1995;377(6548):438–41.

    PubMed  CAS  Google Scholar 

  48. Aon MA, Cortassa S, Marban E, O’Rourke B. Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem. 2003;278(45):44735–44.

    PubMed  CAS  Google Scholar 

  49. Petronilli V, Penzo D, Scorrano L, Bernardi P, Di LF. The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem. 2001;276(15):12030–4.

    PubMed  CAS  Google Scholar 

  50. Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+ overloading, trigger pH- and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2006;290(5):H2024–34.

    PubMed  CAS  Google Scholar 

  51. Penzo D, Petronilli V, Angelin A, et al. Arachidonic acid released by phospholipase A(2) activation triggers Ca(2+)-dependent apoptosis through the mitochondrial pathway. J Biol Chem. 2004;279(24):25219–25.

    PubMed  CAS  Google Scholar 

  52. Goll DE, Thompson VF, Li H, Wei W, Cong J. The calpain system. Physiol Rev. 2003;83(3):731–801.

    PubMed  CAS  Google Scholar 

  53. Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4(7):552–65.

    PubMed  CAS  Google Scholar 

  54. Shulga N, Pastorino JG. Acyl coenzyme A-binding protein augments bid-induced mitochondrial damage and cell death by activating mu-calpain. J Biol Chem. 2006;281(41):30824–33.

    PubMed  CAS  Google Scholar 

  55. Aguilar HI, Botla R, Arora AS, Bronk SF, Gores GJ. Induction of the mitochondrial permeability transition by protease activity in rats: a mechanism of hepatocyte necrosis. Gastroenterology. 1996;110(2):558–66.

    PubMed  CAS  Google Scholar 

  56. Polster BM, Basanez G, Etxebarria A, Hardwick JM, Nicholls DG. Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem. 2005;280(8):6447–54.

    PubMed  CAS  Google Scholar 

  57. Chen M, Won DJ, Krajewski S, Gottlieb RA. Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem. 2002;277(32):29181–6.

    PubMed  CAS  Google Scholar 

  58. Liesa M, Luptak I, Qin F, et al. Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion. Circulation. 2011;124(7):806–13.

    PubMed  CAS  Google Scholar 

  59. Murphy E, Steenbergen C. What makes the mitochondria a killer? Can we condition them to be less destructive? Biochim Biophys Acta. 2011;1813(7):1302–8.

    PubMed  CAS  Google Scholar 

  60. Comelli M, Metelli G, Mavelli I. Downmodulation of mitochondrial F0F1 ATP synthase by diazoxide in cardiac myoblasts: a dual effect of the drug. Am J Physiol Heart Circ Physiol. 2007;292(2):H820–9.

    PubMed  CAS  Google Scholar 

  61. Imahashi K, Schneider MD, Steenbergen C, Murphy E. Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res. 2004;95(7):734–41.

    PubMed  CAS  Google Scholar 

  62. Zhao ZQ, Velez DA, Wang NP, et al. Progressively developed myocardial apoptotic cell death during late phase of reperfusion. Apoptosis. 2001;6(4):279–90.

    PubMed  CAS  Google Scholar 

  63. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res. 2002;55(3):534–43.

    PubMed  CAS  Google Scholar 

  64. Di LF, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: fixing a hole. Cardiovasc Res. 2006;70(2):191–9.

    Google Scholar 

  65. Juhaszova M, Zorov DB, Kim SH, et al. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004;113(11):1535–49.

    PubMed  CAS  Google Scholar 

  66. Garlid KD, Paucek P, Yarov-Yarovoy V, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K  +  channels. Possible mechanism of cardioprotection. Circ Res. 1997;81(6):1072–82.

    PubMed  CAS  Google Scholar 

  67. Costa AD, Quinlan CL, Andrukhiv A, West IC, Jaburek M, Garlid KD. The direct physiological effects of mitoK(ATP) opening on heart mitochondria. Am J Physiol Heart Circ Physiol. 2006;290(1):H406–15.

    PubMed  CAS  Google Scholar 

  68. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol. 2001;280(2):H649–57.

    PubMed  CAS  Google Scholar 

  69. Holmuhamedov EL, Wang L, Terzic A. ATP-sensitive K  +  channel openers prevent Ca2+ overload in rat cardiac mitochondria. J Physiol. 1999;519(Pt 2):347–60.

    PubMed  CAS  Google Scholar 

  70. Andrukhiv A, Costa AD, West IC, Garlid KD. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol. 2006;291(5):H2067–74.

    PubMed  CAS  Google Scholar 

  71. Costantini P, Chernyak BV, Petronilli V, Bernardi P. Selective inhibition of the mitochondrial permeability transition pore at the oxidation-reduction sensitive dithiol by monobromobimane. FEBS Lett. 1995;362(2):239–42.

    PubMed  CAS  Google Scholar 

  72. Costa AD, Jakob R, Costa CL, Andrukhiv K, West IC, Garlid KD. The mechanism by which the mitochondrial ATP-sensitive K  +  channel opening and H2O2 inhibit the mitochondrial permeability transition. J Biol Chem. 2006;281(30):20801–8.

    PubMed  CAS  Google Scholar 

  73. Baines CP, Song CX, Zheng YT, et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003;92(8):873–80.

    PubMed  CAS  Google Scholar 

  74. Heinzel FR, Luo Y, Li X, et al. Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res. 2005;97(6):583–6.

    PubMed  CAS  Google Scholar 

  75. Boengler K, Dodoni G, Rodriguez-Sinovas A, et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res. 2005;67(2):234–44.

    PubMed  CAS  Google Scholar 

  76. Schwanke U, Konietzka I, Duschin A, Li X, Schulz R, Heusch G. No ischemic preconditioning in heterozygous connexin43-deficient mice. Am J Physiol Heart Circ Physiol. 2002;283(4):H1740–2.

    PubMed  CAS  Google Scholar 

  77. McGuinness O, Yafei N, Costi A, Crompton M. The presence of two classes of high-affinity cyclosporin A binding sites in mitochondria. Evidence that the minor component is involved in the opening of an inner-membrane Ca(2+)-dependent pore. Eur J Biochem. 1990;194(2):671–9.

    PubMed  CAS  Google Scholar 

  78. Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005;434(7033):658–62.

    PubMed  CAS  Google Scholar 

  79. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem. 2005;280(19):18558–61.

    PubMed  CAS  Google Scholar 

  80. Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabo I, Zoratti M. Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations J Biol Chem. 1992;267(5):2934–9.

    CAS  Google Scholar 

  81. Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem. 2002;277(38):34793–9.

    PubMed  CAS  Google Scholar 

  82. Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol. 2002;62(1):22–9.

    PubMed  CAS  Google Scholar 

  83. Di LF, Menabo R, Canton M, Barile M, Bernardi P. 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. 2001;276(4):2571–5.

    Google Scholar 

  84. Petronilli V, Miotto G, Canton M, et al. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J. 1999;76(2):725–34.

    PubMed  CAS  Google Scholar 

  85. Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005;434(7033):652–8.

    PubMed  CAS  Google Scholar 

  86. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004;287(4):C817–33.

    PubMed  CAS  Google Scholar 

  87. Bernardi P, Scorrano L, Colonna R, Petronilli V, LF V. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem. 1999;264(3):687–701.

    PubMed  CAS  Google Scholar 

  88. Jauslin ML, Meier T, Smith RA, Murphy MP. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J. 2003;17(13):1972–4.

    PubMed  CAS  Google Scholar 

  89. Ganote CE, Armstrong SC. Effects of CCCP-induced mitochondrial uncoupling and cyclosporin A on cell volume, cell injury and preconditioning protection of isolated rabbit cardiomyocytes. J Mol Cell Cardiol. 2003;35(7):749–59.

    PubMed  CAS  Google Scholar 

  90. Bienengraeber M, Ozcan C, Terzic A. Stable transfection of UCP1 confers resistance to hypoxia/reoxygenation in a heart-derived cell line. J Mol Cell Cardiol. 2003;35(7):861–5.

    PubMed  CAS  Google Scholar 

  91. McLeod CJ, Aziz A, Hoyt Jr RF, McCoy Jr JP, Sack MN. Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia. J Biol Chem. 2005;280(39):33470–6.

    PubMed  CAS  Google Scholar 

  92. Elz JS, Nayler WG. Calcium gain during postischemic reperfusion. The effect of 2,4-dinitrophenol. Am J Pathol. 1988;131(1):137–45.

    PubMed  CAS  Google Scholar 

  93. Ganote C, Armstrong S. Ischaemia and the myocyte cytoskeleton: review and speculation. Cardiovasc Res. 1993;27(8):1387–403.

    PubMed  CAS  Google Scholar 

  94. Silverman HS, Stern MD. Ionic basis of ischaemic cardiac injury: insights from cellular studies. Cardiovasc Res. 1994;28(5):581–97.

    PubMed  CAS  Google Scholar 

  95. Maurel A, Hernandez C, Kunduzova O, et al. Age-dependent increase in hydrogen peroxide production by cardiac monoamine oxidase A in rats. Am J Physiol Heart Circ Physiol. 2003;284(4):H1460–7.

    PubMed  CAS  Google Scholar 

  96. Bianchi P, Pimentel DR, Murphy MP, Colucci WS, Parini A. A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. FASEB J. 2005;19(6):641–3.

    PubMed  CAS  Google Scholar 

  97. Bianchi P, Kunduzova O, Masini E, et al. Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation. 2005;112(21):3297–305.

    PubMed  CAS  Google Scholar 

  98. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. Cardiovasc Res. 1997;33(2):243–57.

    PubMed  CAS  Google Scholar 

  99. Taegtmeyer H, King LM, Jones BE. Energy substrate metabolism, myocardial ischemia, and targets for pharmacotherapy. Am J Cardiol. 1998;82(5A):54K–60.

    PubMed  CAS  Google Scholar 

  100. Stanley WC, Sabbah HN. Metabolic therapy for ischemic heart disease: the rationale for inhibition of fatty acid oxidation. Heart Fail Rev. 2005;10(4):275–9.

    PubMed  Google Scholar 

  101. Lopaschuk GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res. 1988;63(6):1036–43.

    PubMed  CAS  Google Scholar 

  102. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86(5):580–8.

    PubMed  CAS  Google Scholar 

  103. Bertomeu-Gonzalez V, Bouzas-Mosquera A, Kaski JC. Role of trimetazidine in management of ischemic cardiomyopathy. Am J Cardiol. 2006;98(5A):19J–24.

    PubMed  CAS  Google Scholar 

  104. Ramsay RR, Arduini A. The carnitine acyltransferases and their role in modulating acyl-CoA pools. Arch Biochem Biophys. 1993;302(2):307–14.

    PubMed  CAS  Google Scholar 

  105. Arduini A, Mancinelli G, Radatti GL, Dottori S, Molajoni F, Ramsay RR. Role of carnitine and carnitine palmitoyltransferase as integral components of the pathway for membrane phospholipid fatty acid turnover in intact human erythrocytes. J Biol Chem. 1992;267(18):12673–81.

    PubMed  CAS  Google Scholar 

  106. Andrieu-Abadie N, Jaffrezou JP, Hatem S, Laurent G, Levade T, Mercadier JJ. L-carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: role of inhibition of ceramide generation. FASEB J. 1999;13(12):1501–10.

    PubMed  CAS  Google Scholar 

  107. Mutomba MC, Yuan H, Konyavko M, et al. Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine. FEBS Lett. 2000;478(1–2):19–25.

    PubMed  CAS  Google Scholar 

  108. Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T. Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem. 1997;272(6):3324–9.

    PubMed  CAS  Google Scholar 

  109. Nordberg J, Arner ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med. 2001;31(11):1287–312.

    PubMed  CAS  Google Scholar 

  110. Gasdaska PY, Gasdaska JR, Cochran S, Powis G. Cloning and sequencing of a human thioredoxin reductase. FEBS Lett. 1995;373(1):5–9.

    PubMed  CAS  Google Scholar 

  111. Berndt C, Lillig CH, Holmgren A. Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2007;292(3):H1227–36.

    PubMed  CAS  Google Scholar 

  112. Tao L, Jiao X, Gao E, et al. Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis. Circulation. 2006;114(13):1395–402.

    PubMed  CAS  Google Scholar 

  113. Horstkotte J, Perisic T, Schneider M, et al. Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection. Circulation. 2011;124(25):2892–902.

    PubMed  CAS  Google Scholar 

  114. Halestrap AP, Kerr PM, Javadov S, Woodfield KY. Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart. Biochim Biophys Acta. 1998;1366(1–2):79–94.

    PubMed  CAS  Google Scholar 

  115. Di Lisa F, Canton M, Menabò R, Kaludercic N, Bernardi P. Mitochondria and cardioprotection. Heart Fail Rev. 2007;12(3–4):249–60.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ, USA

    José Marín-García M.D.

Authors
  1. José Marín-García M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Marín-García, J. (2013). Role of Mitochondria in Ischemia and Cardioprotection. In: Mitochondria and Their Role in Cardiovascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4599-9_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-4599-9_16

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4614-4598-2

  • Online ISBN: 978-1-4614-4599-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation