Cellular and Molecular Life Sciences

, Volume 74, Issue 15, pp 2795–2813 | Cite as

Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?

  • Sabzali Javadov
  • Sehwan Jang
  • Rebecca Parodi-Rullán
  • Zaza Khuchua
  • Andrey V. Kuznetsov
Review

Abstract

Growing number of studies provide strong evidence that the mitochondrial permeability transition pore (PTP), a non-selective channel in the inner mitochondrial membrane, is involved in the pathogenesis of cardiac ischemia–reperfusion and can be targeted to attenuate reperfusion-induced damage to the myocardium. The molecular identity of the PTP remains unknown and cyclophilin D is the only protein commonly accepted as a major regulator of the PTP opening. Therefore, cyclophilin D is an attractive target for pharmacological or genetic therapies to reduce ischemia–reperfusion injury in various animal models and humans. Most animal studies demonstrated cardioprotective effects of PTP inhibition; however, a recent large clinical trial conducted by international groups demonstrated that cyclosporine A, a cyclophilin D inhibitor, failed to protect the heart in patients with myocardial infarction. These studies, among others, raise the question of whether cyclophilin D, which plays an important physiological role in the regulation of cell metabolism and mitochondrial bioenergetics, is a viable target for cardioprotection. This review discusses previous studies to provide comprehensive information on the physiological role of cyclophilin D as well as PTP opening in the cell that can be taken into consideration for the development of new PTP inhibitors.

Keywords

Ischemia–reperfusion injury Cardioprotection Mitochondrial permeability transition pores Cyclophilin D Oxidative stress 

Abbreviations

ANT

Adenine nucleotide translocase

CRC

Ca2+ retention capacity

CsA

Cyclosporine A

CypD

Cyclophilin D

ETC

Electron transport chain

FAO

Fatty acid oxidation

Hsp60

Heat-shock protein 60

IFM

Interfibrillar mitochondria

IMM

Inner mitochondrial membrane

IR

Ischemia–reperfusion

KO

Knockout

ΔΨm

Mitochondrial membrane potential

MEFs

Mouse embryonic fibroblasts

MI

Myocardial infarction

mtDNA

Mitochondrial DNA

NO

Nitric oxide

PCI

Percutaneous coronary intervention

Pi

Inorganic phosphate

PiC

Phosphate carrier

PPARα

Peroxisome proliferator-activated receptor alpha

PPIase

Peptidyl-prolyl cis-trans isomerase

Ppif

CypD gene

PTM

Post-translational modification

PTP

Permeability transition pore

ROS

Reactive oxygen species

SfA

Sanglifehrin A

SPG7

Spastic paraplegia 7

SSM

Subsarcolemmal mitochondria

TCA

Tricarboxylic acid

TRAP1

Tumor necrosis factor receptor-associated protein 1

VDAC

Voltage-dependent anion channel

WT

Wild type

Notes

Acknowledgements

The authors apologize that they could not cite all important studies in this field due to space restriction. This study was supported by the NHLBI NIH Grants SC1HL118669 (to SJ).

References

  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ et al (2016) Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 133:e38–e360PubMedCrossRefGoogle Scholar
  2. 2.
    Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135PubMedCrossRefGoogle Scholar
  3. 3.
    Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88:581–609PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kloner RA, Schwartz Longacre L (2011) State of the science of cardioprotection: challenges and opportunities–proceedings of the 2010 NHLBI Workshop on Cardioprotection. J Cardiovasc Pharmacol Ther 16:223–232PubMedCrossRefGoogle Scholar
  5. 5.
    Ertracht O, Malka A, Atar S, Binah O (2014) The mitochondria as a target for cardioprotection in acute myocardial ischemia. Pharmacol Ther 142:33–40PubMedCrossRefGoogle Scholar
  6. 6.
    Hausenloy DJ, Yellon DM (2013) Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 123:92–100PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Walters AM, Porter GA Jr, Brookes PS (2012) Mitochondria as a drug target in ischemic heart disease and cardiomyopathy. Circ Res 111:1222–1236PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res 61:372–385PubMedCrossRefGoogle Scholar
  9. 9.
    Bernardi P, Di Lisa F (2015) The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol 78:100–106PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Griffiths EJ, Halestrap AP (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 307(Pt 1):93–98PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kerr PM, Suleiman MS, Halestrap AP (1999) Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am J Physiol 276:H496–H502PubMedGoogle Scholar
  12. 12.
    Kitakaze M, Takashima S, Funaya H, Minamino T, Node K et al (1997) Temporary acidosis during reperfusion limits myocardial infarct size in dogs. Am J Physiol 272:H2071–H2078PubMedGoogle Scholar
  13. 13.
    Javadov S, Huang C, Kirshenbaum L, Karmazyn M (2005) NHE-1 inhibition improves impaired mitochondrial permeability transition and respiratory function during postinfarction remodelling in the rat. J Mol Cell Cardiol 38:135–143PubMedCrossRefGoogle Scholar
  14. 14.
    Javadov S, Purdham DM, Zeidan A, Karmazyn M (2006) NHE-1 inhibition improves cardiac mitochondrial function through regulation of mitochondrial biogenesis during postinfarction remodeling. Am J Physiol Heart Circ Physiol 291:H1722–H1730PubMedCrossRefGoogle Scholar
  15. 15.
    Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG et al (2008) NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res 77:416–424PubMedCrossRefGoogle Scholar
  16. 16.
    Halestrap AP, Richardson AP (2015) The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol 78:129–141PubMedCrossRefGoogle Scholar
  17. 17.
    Javadov S, Karmazyn M, Escobales N (2009) Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J Pharmacol Exp Ther 330:670–678PubMedCrossRefGoogle Scholar
  18. 18.
    Ong SB, Samangouei P, Kalkhoran SB, Hausenloy DJ (2015) The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. J Mol Cell Cardiol 78:23–34PubMedCrossRefGoogle Scholar
  19. 19.
    Alam MR, Baetz D, Ovize M (2015) Cyclophilin D and myocardial ischemia-reperfusion injury: a fresh perspective. J Mol Cell Cardiol 78:80–89PubMedCrossRefGoogle Scholar
  20. 20.
    Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D et al (2015) Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 373:1021–1031PubMedCrossRefGoogle Scholar
  21. 21.
    Paillard M, Tubbs E, Thiebaut PA, Gomez L, Fauconnier J et al (2013) Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury. Circulation 128:1555–1565PubMedCrossRefGoogle Scholar
  22. 22.
    Smaili SS, Stellato KA, Burnett P, Thomas AP, Gaspers LD (2001) Cyclosporin A inhibits inositol 1,4,5-trisphosphate-dependent Ca2+ signals by enhancing Ca2+ uptake into the endoplasmic reticulum and mitochondria. J Biol Chem 276:23329–23340PubMedCrossRefGoogle Scholar
  23. 23.
    Tavecchio M, Lisanti S, Lam A, Ghosh JC, Martin NM et al (2013) Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility. J Biol Chem 288:5553–5561PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Radhakrishnan J, Bazarek S, Chandran B, Gazmuri RJ (2015) Cyclophilin-D: a resident regulator of mitochondrial gene expression. Faseb J 29:2734–2748PubMedCrossRefGoogle Scholar
  25. 25.
    Elrod JW, Wong R, Mishra S, Vagnozzi RJ, Sakthievel B et al (2010) Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J Clin Invest 120:3680–3687PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Tavecchio M, Lisanti S, Bennett MJ, Languino LR, Altieri DC (2015) Deletion of Cyclophilin D impairs beta-oxidation and promotes glucose metabolism. Sci Rep 5:15981PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Giorgio V, Bisetto E, Soriano ME, Dabbeni-Sala F, Basso E et al (2009) Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Chinopoulos C, Konrad C, Kiss G, Metelkin E, Torocsik B et al (2011) Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels. Febs J 278:1112–1125PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Tubbs E, Theurey P, Vial G, Bendridi N, Bravard A et al (2014) Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance. Diabetes 63:3279–3294PubMedCrossRefGoogle Scholar
  30. 30.
    Taddeo EP, Laker RC, Breen DS, Akhtar YN, Kenwood BM et al (2014) Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Mol Metab 3:124–134PubMedCrossRefGoogle Scholar
  31. 31.
    Feng D, Tang Y, Kwon H, Zong H, Hawkins M et al (2011) High-fat diet-induced adipocyte cell death occurs through a cyclophilin D intrinsic signaling pathway independent of adipose tissue inflammation. Diabetes 60:2134–2143PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wang DZ, Jones AW, Wang WZ, Wang M, Korthuis RJ (2016) Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level. Am J Physiol Gastrointest Liver Physiol 310:G747–G756PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Haworth RA, Hunter DR (1979) The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch Biochem Biophys 195:460–467PubMedCrossRefGoogle Scholar
  34. 34.
    Le Quoc K, Le Quoc D (1988) Involvement of the ADP/ATP carrier in calcium-induced perturbations of the mitochondrial inner membrane permeability: importance of the orientation of the nucleotide binding site. Arch Biochem Biophys 265:249–257PubMedCrossRefGoogle Scholar
  35. 35.
    Halestrap AP, Davidson AM (1990) Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J 268:153–160PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Brustovetsky N, Klingenberg M (1996) Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. BioChemistry 35:8483–8488PubMedCrossRefGoogle Scholar
  37. 37.
    Beutner G, Ruck A, Riede B, Welte W, Brdiczka D (1996) Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore. FEBS Lett 396:189–195PubMedCrossRefGoogle Scholar
  38. 38.
    Szabo I, Zoratti M (1993) The mitochondrial permeability transition pore may comprise VDAC molecules. I. Binary structure and voltage dependence of the pore. FEBS Lett 330:201–205PubMedCrossRefGoogle Scholar
  39. 39.
    Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J et al (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA et al (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280:18558–18561PubMedCrossRefGoogle Scholar
  41. 41.
    Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K et al (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658PubMedCrossRefGoogle Scholar
  42. 42.
    Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R et al (2015) Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. J Mol Cell Cardiol 78:142–153PubMedCrossRefGoogle Scholar
  44. 44.
    Leung AW, Varanyuwatana P, Halestrap AP (2008) The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem 283:26312–26323PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Varanyuwatana P, Halestrap AP (2012) The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. Mitochondrion 12:120–125PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Gutierrez-Aguilar M, Douglas DL, Gibson AK, Domeier TL, Molkentin JD et al (2014) Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. J Mol Cell Cardiol 72:316–325PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kwong JQ, Davis J, Baines CP, Sargent MA, Karch J et al (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209–1217PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Shanmughapriya S, Rajan S, Hoffman NE, Higgins AM, Tomar D et al (2015) SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore. Mol Cell 60:47–62PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Bernardi P, Forte M (2015) Commentary: SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Front Physiol 6:320PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Jonckheere AI, Smeitink JA, Rodenburg RJ (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35:211–225PubMedCrossRefGoogle Scholar
  51. 51.
    Ko YH, Delannoy M, Hullihen J, Chiu W, Pedersen PL (2003) Mitochondrial ATP synthasome. Cristae-enriched membranes and a multiwell detergent screening assay yield dispersed single complexes containing the ATP synthase and carriers for Pi and ADP/ATP. J Biol Chem 278:12305–12309PubMedCrossRefGoogle Scholar
  52. 52.
    Wittig I, Schagger H (2008) Structural organization of mitochondrial ATP synthase. Biochim Biophys Acta 1777: 592–598Google Scholar
  53. 53.
    Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M et al (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA et al (2014) 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 111:10580–10585PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Azarashvili T, Odinokova I, Bakunts A, Ternovsky V, Krestinina O et al (2014) Potential role of subunit c of F0F1-ATPase and subunit c of storage body in the mitochondrial permeability transition. Effect of the phosphorylation status of subunit c on pore opening. Cell Calcium 55:69–77PubMedCrossRefGoogle Scholar
  56. 56.
    Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Masgras I, Rasola A, Bernardi P (2012) Induction of the permeability transition pore in cells depleted of mitochondrial DNA. Biochim Biophys Acta 1817:1860–1866PubMedCrossRefGoogle Scholar
  58. 58.
    Lee J, Kim SS (2010) An overview of cyclophilins in human cancers. J Int Med Res 38:1561–1574PubMedCrossRefGoogle Scholar
  59. 59.
    Gutierrez-Aguilar M, Baines CP (2015) Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta 1850:2041–2047PubMedCrossRefGoogle Scholar
  60. 60.
    Johnson N, Khan A, Virji S, Ward JM, Crompton M (1999) Import and processing of heart mitochondrial cyclophilin D. Eur J Biochem 263:353–359PubMedCrossRefGoogle Scholar
  61. 61.
    Galat A (1993) Peptidylproline cis-trans-isomerases: immunophilins. Eur J Biochem 216:689–707PubMedCrossRefGoogle Scholar
  62. 62.
    Lodish HF, Kong N (1991) Cyclosporin A inhibits an initial step in folding of transferrin within the endoplasmic reticulum. J Biol Chem 266:14835–14838PubMedGoogle Scholar
  63. 63.
    Tanveer A, Virji S, Andreeva L, Totty NF, Hsuan JJ et al (1996) Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2 + and oxidant stress. Eur J Biochem 238:166–172PubMedCrossRefGoogle Scholar
  64. 64.
    Altschuld RA, Hohl CM, Castillo LC, Garleb AA, Starling RC et al (1992) Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am J Physiol 262:H1699–H1704PubMedGoogle Scholar
  65. 65.
    Ichas F, Mazat JP (1998) From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta 1366:33–50PubMedCrossRefGoogle Scholar
  66. 66.
    Bernardi P, Petronilli V (1996) The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal. J Bioenerg Biomembr 28:131–138PubMedCrossRefGoogle Scholar
  67. 67.
    Huser J, Blatter LA (1999) Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore. Biochem J 343(Pt 2):311–317PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Ichas F, Jouaville LS, Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89:1145–1153PubMedCrossRefGoogle Scholar
  69. 69.
    De Marchi E, Bonora M, Giorgi C, Pinton P (2014) The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux. Cell Calcium 56:1–13PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wei AC, Liu T, Cortassa S, Winslow RL, O’Rourke B (2011) Mitochondrial Ca2 + influx and efflux rates in guinea pig cardiac mitochondria: low and high affinity effects of cyclosporine A. Biochim Biophys Acta 1813:1373–1381PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Olbrich HG, Geerts H, Waldmann U, Mutschler E, Ver Donck L et al (1991) The effect of cyclosporine on electrically paced isolated rat cardiomyocytes. Transplantation 51:972–976PubMedCrossRefGoogle Scholar
  72. 72.
    Griffiths EJ, Halestrap AP (1993) Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 25:1461–1469PubMedCrossRefGoogle Scholar
  73. 73.
    Montero M, Lobaton CD, Gutierrez-Fernandez S, Moreno A, Alvarez J (2004) Calcineurin-independent inhibition of mitochondrial Ca2 + uptake by cyclosporin A. Br J Pharmacol 141:263–268PubMedCrossRefGoogle Scholar
  74. 74.
    Garcia-Dorado D, Ruiz-Meana M, Inserte J, Rodriguez-Sinovas A, Piper HM (2012) Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res 94:168–180PubMedCrossRefGoogle Scholar
  75. 75.
    Reddy PA, Atreya CD (1999) Identification of simian cyclophilin A as a calreticulin-binding protein in yeast two-hybrid screen and demonstration of cyclophilin A interaction with calreticulin. Int J Biol Macromol 25:345–351PubMedCrossRefGoogle Scholar
  76. 76.
    Fournier N, Ducet G, Crevat A (1987) Action of cyclosporine on mitochondrial calcium fluxes. J Bioenerg Biomembr 19:297–303PubMedCrossRefGoogle Scholar
  77. 77.
    Shang W, Gao H, Lu F, Ma Q, Fang H et al (2016) Cyclophilin D regulates mitochondrial flashes and metabolism in cardiac myocytes. J Mol Cell Cardiol 91:63–71PubMedCrossRefGoogle Scholar
  78. 78.
    Li K, Zhang W, Fang H, Xie W, Liu J et al (2012) Superoxide flashes reveal novel properties of mitochondrial reactive oxygen species excitability in cardiomyocytes. Biophys J 102:1011–1021PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Fang H, Chen M, Ding Y, Shang W, Xu J et al (2011) Imaging superoxide flash and metabolism-coupled mitochondrial permeability transition in living animals. Cell Res 21:1295–1304PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Tarasov AI, Griffiths EJ, Rutter GA (2012) Regulation of ATP production by mitochondrial Ca(2+). Cell Calcium 52:28–35PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Menazza S, Wong R, Nguyen T, Wang G, Gucek M et al (2013) CypD(-/-) hearts have altered levels of proteins involved in Krebs cycle, branch chain amino acid degradation and pyruvate metabolism. J Mol Cell Cardiol 56:81–90PubMedCrossRefGoogle Scholar
  82. 82.
    Jang S, Lewis TS, Powers C, Khuchua Z, Baines CP et al (2016) Elucidating mitochondrial electron transport chain supercomplexes in the heart during ischemia-reperfusion. Antioxid Redox Signal. doi: 10.1089/ars.2016.6635
  83. 83.
    Halestrap AP (1994) Regulation of mitochondrial metabolism through changes in matrix volume. Biochem Soc Trans 22:522–529PubMedCrossRefGoogle Scholar
  84. 84.
    Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z (2009) Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore. Eur J Pharmacol 604:111–116PubMedCrossRefGoogle Scholar
  85. 85.
    Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS et al (2010) Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci USA 107:726–731PubMedCrossRefGoogle Scholar
  86. 86.
    Bao H, Ge Y, Zhuang S, Dworkin LD, Liu Z et al (2012) Inhibition of glycogen synthase kinase-3beta prevents NSAID-induced acute kidney injury. Kidney Int 81:662–673PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Kohr MJ, Sun J, Aponte A, Wang G, Gucek M et al (2011) Simultaneous measurement of protein oxidation and S-nitrosylation during preconditioning and ischemia/reperfusion injury with resin-assisted capture. Circ Res 108:418–426PubMedCrossRefGoogle Scholar
  88. 88.
    Sun J, Steenbergen C, Murphy E (2006) S-nitrosylation: NO-related redox signaling to protect against oxidative stress. Antioxid Redox Signal 8:1693–1705PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Burwell LS, Brookes PS (2008) Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury. Antioxid Redox Signal 10:579–599PubMedCrossRefGoogle Scholar
  90. 90.
    Pagliaro P, Moro F, Tullio F, Perrelli MG, Penna C (2011) Cardioprotective pathways during reperfusion: focus on redox signaling and other modalities of cell signaling. Antioxid Redox Signal 14:833–850PubMedCrossRefGoogle Scholar
  91. 91.
    Sun J, Murphy E (2010) Protein S-nitrosylation and cardioprotection. Circ Res 106:285–296PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Vieira HL, Belzacq AS, Haouzi D, Bernassola F, Cohen I et al (2001) The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene 20:4305–4316PubMedCrossRefGoogle Scholar
  93. 93.
    Martin LJ, Adams NA, Pan Y, Price A, Wong M (2011) The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation. J Neurosci 31:359–370PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Nguyen TT, Stevens MV, Kohr M, Steenbergen C, Sack MN et al (2011) Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore. J Biol Chem 286:40184–40192PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Linard D, Kandlbinder A, Degand H, Morsomme P, Dietz KJ et al (2009) Redox characterization of human cyclophilin D: identification of a new mammalian mitochondrial redox sensor? Arch Biochem Biophys 491:39–45PubMedCrossRefGoogle Scholar
  96. 96.
    Lopez-Erauskin J, Galino J, Bianchi P, Fourcade S, Andreu AL et al (2012) Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain 135:3584–3598PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Folda A, Citta A, Scalcon V, Cali T, Zonta F et al (2016) Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State. Sci Rep 6:23071Google Scholar
  98. 98.
    Shulga N, Wilson-Smith R, Pastorino JG (2010) Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria. J Cell Sci 123:894–902PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Shulga N, Pastorino JG (2010) Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3. J Cell Sci 123:4117–4127PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM et al (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging 2:914–923PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Parodi-Rullan R, Barreto-Torres G, Ruiz L, Casasnovas J, Javadov S (2012) Direct renin inhibition exerts an anti-hypertrophic effect associated with improved mitochondrial function in post-infarction heart failure in diabetic rats. Cell Physiol Biochem 29:841–850PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Bochaton T, Crola-Da-Silva C, Pillot B, Villedieu C, Ferreras L et al (2015) Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D. J Mol Cell Cardiol 84:61–69PubMedCrossRefGoogle Scholar
  103. 103.
    Nguyen TT, Wong R, Menazza S, Sun J, Chen Y et al (2013) Cyclophilin D modulates mitochondrial acetylome. Circ Res 113:1308–1319PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Woodfield K, Ruck A, Brdiczka D, Halestrap AP (1998) Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J 336(Pt 2):287–290PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Crompton M, Virji S, Ward JM (1998) Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 258:729–735PubMedCrossRefGoogle Scholar
  106. 106.
    McStay GP, Clarke SJ, Halestrap AP (2002) Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J 367:541–548PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Majima E, Koike H, Hong YM, Shinohara Y, Terada H (1993) Characterization of cysteine residues of mitochondrial ADP/ATP carrier with the SH-reagents eosin 5-maleimide and N-ethylmaleimide. J Biol Chem 268:22181–22187PubMedGoogle Scholar
  108. 108.
    Costantini P, Chernyak BV, Petronilli V, Bernardi P (1996) Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites. J Biol Chem 271:6746–6751PubMedCrossRefGoogle Scholar
  109. 109.
    Halestrap AP, Woodfield KY, Connern CP (1997) Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem 272:3346–3354PubMedCrossRefGoogle Scholar
  110. 110.
    Halestrap AP, Brennerb C (2003) The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem 10:1507–1525PubMedCrossRefGoogle Scholar
  111. 111.
    Kallen J, Sedrani R, Zenke G, Wagner J (2005) Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6 A resolution. J Biol Chem 280:21965–21971PubMedCrossRefGoogle Scholar
  112. 112.
    Clarke SJ, McStay GP, Halestrap AP (2002) 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 277:34793–34799PubMedCrossRefGoogle Scholar
  113. 113.
    Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S et al (2012) p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149:1536–1548PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Chen B, Xu M, Zhang H, Wang JX, Zheng P et al (2013) Cisplatin-induced non-apoptotic death of pancreatic cancer cells requires mitochondrial cyclophilin-D-p53 signaling. Biochem Biophys Res Commun 437:526–531PubMedCrossRefGoogle Scholar
  115. 115.
    Zhao LP, Ji C, Lu PH, Li C, Xu B et al (2013) Oxygen glucose deprivation (OGD)/re-oxygenation-induced in vitro neuronal cell death involves mitochondrial cyclophilin-D/P53 signaling axis. Neurochem Res 38:705–713PubMedCrossRefGoogle Scholar
  116. 116.
    Zhen YF, Wang GD, Zhu LQ, Tan SP, Zhang FY et al (2014) P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol 229:1475–1483PubMedCrossRefGoogle Scholar
  117. 117.
    Bergeaud M, Mathieu L, Guillaume A, Moll UM, Mignotte B et al (2013) Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F(1)F0-ATP synthase. Cell Cycle 12:2781–2793PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Hernandez JS, Barreto-Torres G, Kuznetsov AV, Khuchua Z, Javadov S (2014) Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria. J Cell Mol Med 18:709–720PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Karch J, Molkentin JD (2012) Is p53 the long-sought molecular trigger for cyclophilin D-regulated mitochondrial permeability transition pore formation and necrosis? Circ Res 111:1258–1260PubMedCrossRefGoogle Scholar
  120. 120.
    Starkov AA (2010) The molecular identity of the mitochondrial Ca2 + sequestration system. Febs J 277:3652–3663PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    McGee AM, Baines CP (2011) Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death. Biochem J 433:119–125PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Barreto-Torres G, Hernandez JS, Jang S, Rodriguez-Munoz AR, Torres-Ramos CA et al (2015) The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPARalpha-cyclophilin D interaction in cardiomyocytes. Am J Physiol Heart Circ Physiol 308:H749–H758PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Barreto-Torres G, Javadov S (2016) Possible role of interaction between PPARalpha and Cyclophilin D in cardioprotection of AMPK against in vivo ischemia-reperfusion in rats. PPAR Res 2016:9282087Google Scholar
  124. 124.
    Li Y, Johnson N, Capano M, Edwards M, Crompton M (2004) Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem J 383:101–109PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Schubert A, Grimm S (2004) Cyclophilin D, a component of the permeability transition-pore, is an apoptosis repressor. Cancer Res 64:85–93PubMedCrossRefGoogle Scholar
  126. 126.
    Javadov S, Hunter JC, Barreto-Torres G, Parodi-Rullan R (2011) Targeting the mitochondrial permeability transition: cardiac ischemia-reperfusion versus carcinogenesis. Cell Physiol Biochem 27:179–190PubMedCrossRefGoogle Scholar
  127. 127.
    Machida K, Ohta Y, Osada H (2006) Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells. J Biol Chem 281:14314–14320PubMedCrossRefGoogle Scholar
  128. 128.
    Ghosh JC, Siegelin MD, Dohi T, Altieri DC (2010) Heat shock protein 60 regulation of the mitochondrial permeability transition pore in tumor cells. Cancer Res 70:8988–8993PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Kang BH, Plescia J, Dohi T, Rosa J, Doxsey SJ et al (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131:257–270PubMedCrossRefGoogle Scholar
  130. 130.
    Schusdziarra C, Blamowska M, Azem A, Hell K (2013) Methylation-controlled J-protein MCJ acts in the import of proteins into human mitochondria. Hum Mol Genet 22:1348–1357PubMedCrossRefGoogle Scholar
  131. 131.
    Sinha D, D’Silva P (2014) Chaperoning mitochondrial permeability transition: regulation of transition pore complex by a J-protein, DnaJC15. Cell Death Dis 5:e1101PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Chen SH, Li DL, Yang F, Wu Z, Zhao YY et al (2014) Gemcitabine-induced pancreatic cancer cell death is associated with MST1/cyclophilin D mitochondrial complexation. Biochimie 103:71–79PubMedCrossRefGoogle Scholar
  133. 133.
    Eliseev RA, Malecki J, Lester T, Zhang Y, Humphrey J et al (2009) Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect. J Biol Chem 284:9692–9699PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Takahashi N, Hayano T, Suzuki M (1989) Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 337:473–475PubMedCrossRefGoogle Scholar
  135. 135.
    Flanagan WM, Corthesy B, Bram RJ, Crabtree GR (1991) Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352:803–807PubMedCrossRefGoogle Scholar
  136. 136.
    Calne RY, White DJ, Thiru S, Evans DB, McMaster P et al (1978) Cyclosporin A in patients receiving renal allografts from cadaver donors. The Lancet 2:1323–1327CrossRefGoogle Scholar
  137. 137.
    Calne RY, Rolles K, White DJ, Thiru S, Evans DB et al (1979) Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. The Lancet 2:1033–1036CrossRefGoogle Scholar
  138. 138.
    Thiel G, Brunner FP, Hermle M, Stahl RA, Mihatsch MJ (1986) Effect of cyclosporine A on ischemic renal failure in the rat. Clin Nephrol 25(Suppl 1):S155–S161PubMedGoogle Scholar
  139. 139.
    Jablonski P, Harrison C, Howden B, Rae D, Tavanlis G et al (1986) Cyclosporine and the ischemic rat kidney. Transplantation 41:147–151PubMedCrossRefGoogle Scholar
  140. 140.
    Hayashi T, Nagasue N, Kohno H, Chang YC, Nakamura T (1988) Beneficial effect of cyclosporine pretreatment in preventing ischemic damage to the liver in dogs. Transplantation 46:923–924PubMedGoogle Scholar
  141. 141.
    Kawano K, Kim YI, Kaketani K, Kobayashi M (1989) The beneficial effect of cyclosporine on liver ischemia in rats. Transplantation 48:759–764PubMedCrossRefGoogle Scholar
  142. 142.
    Griffiths EJ, Halestrap AP (1991) Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. Biochem J 274(Pt 2):611–614PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Nazareth W, Yafei N, Crompton M (1991) Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol 23:1351–1354PubMedCrossRefGoogle Scholar
  144. 144.
    Gomez L, Chavanis N, Argaud L, Chalabreysse L, Gateau-Roesch O et al (2005) Fas-independent mitochondrial damage triggers cardiomyocyte death after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 289:H2153–H2158PubMedCrossRefGoogle Scholar
  145. 145.
    Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R (2010) Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105:771–785PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM (2002) Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res 55:534–543PubMedCrossRefGoogle Scholar
  147. 147.
    Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH et al (2003) Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol 549:513–524PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Weinbrenner C, Liu GS, Downey JM, Cohen MV (1998) Cyclosporine A limits myocardial infarct size even when administered after onset of ischemia. Cardiovasc Res 38:676–684PubMedCrossRefGoogle Scholar
  149. 149.
    Argaud L, Gateau-Roesch O, Muntean D, Chalabreysse L, Loufouat J et al (2005) Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 38:367–374PubMedCrossRefGoogle Scholar
  150. 150.
    Leshnower BG, Kanemoto S, Matsubara M, Sakamoto H, Hinmon R et al (2008) Cyclosporine preserves mitochondrial morphology after myocardial ischemia/reperfusion independent of calcineurin inhibition. Ann Thorac Surg 86:1286–1292PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Skyschally A, Schulz R, Heusch G (2010) Cyclosporine A at reperfusion reduces infarct size in pigs. Cardiovasc Drugs Ther 24:85–87PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Zalewski J, Claus P, Bogaert J, Driessche NV, Driesen RB et al (2015) Cyclosporine A reduces microvascular obstruction and preserves left ventricular function deterioration following myocardial ischemia and reperfusion. Basic Res Cardiol 110:18PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Kay JE, Moore AL, Doe SE, Benzie CR, Schonbrunner R et al (1990) The mechanism of action of FK 506. Transplant Proc 22:96–99PubMedGoogle Scholar
  154. 154.
    Sloan RC, Moukdar F, Frasier CR, Patel HD, Bostian PA et al (2012) Mitochondrial permeability transition in the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented reperfusion injury. J Mol Cell Cardiol 52:1009–1018PubMedCrossRefGoogle Scholar
  155. 155.
    Gomez L, Thibault H, Gharib A, Dumont JM, Vuagniaux G et al (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–H1661PubMedCrossRefGoogle Scholar
  156. 156.
    Lim WY, Messow CM, Berry C (2012) Cyclosporin variably and inconsistently reduces infarct size in experimental models of reperfused myocardial infarction: a systematic review and meta-analysis. Br J Pharmacol 165:2034–2043PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Karlsson LO, Zhou AX, Larsson E, Astrom-Olsson K, Mansson C et al (2010) Cyclosporine does not reduce myocardial infarct size in a porcine ischemia-reperfusion model. J Cardiovasc Pharmacol Ther 15:182–189PubMedCrossRefGoogle Scholar
  158. 158.
    Lie RH, Stoettrup N, Sloth E, Hasenkam JM, Kroyer R et al (2010) Post-conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model. Acta Anaesthesiol Scand 54:804–813PubMedCrossRefGoogle Scholar
  159. 159.
    Kuznetsov AV, Margreiter R (2009) Heterogeneity of mitochondria and mitochondrial function within cells as another level of mitochondrial complexity. Int J Mol Sci 10:1911–1929PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Hollander JM, Thapa D, Shepherd DL (2014) Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies. Am J Physiol Heart Circ Physiol 307:H1–H14PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Palmer JW, Tandler B, Hoppel CL (1986) Heterogeneous response of subsarcolemmal heart mitochondria to calcium. Am J Physiol 250:H741–H748PubMedGoogle Scholar
  162. 162.
    Kuznetsov AV, Troppmair J, Sucher R, Hermann M, Saks V, et al. (2006) Mitochondrial subpopulations and heterogeneity revealed by confocal imaging: possible physiological role? Biochim Biophys Acta 1757: 686–691Google Scholar
  163. 163.
    Arieli Y, Gursahani H, Eaton MM, Hernandez LA, Schaefer S (2004) Gender modulation of Ca(2+) uptake in cardiac mitochondria. J Mol Cell Cardiol 37:507–513PubMedCrossRefGoogle Scholar
  164. 164.
    Milerova M, Drahota Z, Chytilova A, Tauchmannova K, Houstek J et al (2016) Sex difference in the sensitivity of cardiac mitochondrial permeability transition pore to calcium load. Mol Cell Biochem 412:147–154PubMedCrossRefGoogle Scholar
  165. 165.
    Colom B, Oliver J, Roca P, Garcia-Palmer FJ (2007) Caloric restriction and gender modulate cardiac muscle mitochondrial H2O2 production and oxidative damage. Cardiovasc Res 74:456–465PubMedCrossRefGoogle Scholar
  166. 166.
    Vijay V, Han T, Moland CL, Kwekel JC, Fuscoe JC et al (2015) Sexual dimorphism in the expression of mitochondria-related genes in rat heart at different ages. PLoS One 10:e0117047PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Milerova M, Charvatova Z, Skarka L, Ostadalova I, Drahota Z et al (2010) Neonatal cardiac mitochondria and ischemia/reperfusion injury. Mol Cell Biochem 335:147–153PubMedCrossRefGoogle Scholar
  168. 168.
    Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662PubMedCrossRefGoogle Scholar
  169. 169.
    Roy S, Sileikyte J, Neuenswander B, Hedrick MP, Chung TD et al (2016) N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem 11:283–288PubMedCrossRefGoogle Scholar
  170. 170.
    Fancelli D, Abate A, Amici R, Bernardi P, Ballarini M et al (2014) Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo. J Med Chem 57:5333–5347PubMedCrossRefGoogle Scholar
  171. 171.
    Martin LJ, Fancelli D, Wong M, Niedzwiecki M, Ballarini M, et al. (2014) GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis. Front Cell Neurosci 8: 433Google Scholar
  172. 172.
    Richardson AP, Halestrap AP (2016) Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity. Biochem J 473:1129–1140PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Roy S, Sileikyte J, Schiavone M, Neuenswander B, Argenton F et al (2015) Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem 10:1655–1671PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Ibanez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1454–1471PubMedCrossRefGoogle Scholar
  175. 175.
    Bell RM, Botker HE, Carr RD, Davidson SM, Downey JM et al (2016) 9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection. Basic Res Cardiol 111:41PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Miura T, Miki T (2008) Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol 103:501–513PubMedCrossRefGoogle Scholar
  177. 177.
    Downey JM, Cohen MV (2009) Why do we still not have cardioprotective drugs? Circ J 73:1171–1177PubMedCrossRefGoogle Scholar
  178. 178.
    Magid DJ, Wang Y, Herrin J, McNamara RL, Bradley EH et al (2005) Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA 294:803–812PubMedCrossRefGoogle Scholar
  179. 179.
    Schneider A, Ad N, Izhar U, Khaliulin I, Borman JB et al (2003) Protection of myocardium by cyclosporin A and insulin: in vitro simulated ischemia study in human myocardium. Ann Thorac Surg 76:1240–1245PubMedCrossRefGoogle Scholar
  180. 180.
    Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM (2005) Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Am J Physiol Heart Circ Physiol 289:H237–H242PubMedCrossRefGoogle Scholar
  181. 181.
    Piot C, Croisille P, Staat P, Thibault H, Rioufol G et al (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481PubMedCrossRefGoogle Scholar
  182. 182.
    Hausenloy D, Kunst G, Boston-Griffiths E, Kolvekar S, Chaubey S et al (2014) The effect of cyclosporin-A on peri-operative myocardial injury in adult patients undergoing coronary artery bypass graft surgery: a randomised controlled clinical trial. Heart 100:544–549PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Chiari P, Angoulvant D, Mewton N, Desebbe O, Obadia JF et al (2014) Cyclosporine protects the heart during aortic valve surgery. Anesthesiology 121:232–238PubMedCrossRefGoogle Scholar
  184. 184.
    Ghaffari S, Kazemi B, Toluey M, Sepehrvand N (2013) The effect of prethrombolytic cyclosporine-A injection on clinical outcome of acute anterior ST-elevation myocardial infarction. Cardiovasc Ther 31:e34–e39PubMedCrossRefGoogle Scholar
  185. 185.
    Mewton N, Cung TT, Morel O, Cayla G, Bonnefoy-Cudraz E et al (2015) Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial). Am Heart J 169(758–766):e756Google Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  • Sabzali Javadov
    • 1
  • Sehwan Jang
    • 1
  • Rebecca Parodi-Rullán
    • 1
  • Zaza Khuchua
    • 2
  • Andrey V. Kuznetsov
    • 3
  1. 1.Department of Physiology, School of MedicineUniversity of Puerto RicoSan JuanPuerto Rico
  2. 2.Cincinnati Children’s Research FoundationUniversity of CincinnatiCincinnatiUSA
  3. 3.Cardiac Surgery Research Laboratory, Department of Cardiac SurgeryInnsbruck Medical UniversityInnsbruckAustria

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