Mitochondrial involvement in myocyte death and heart failure

Heart Failure Reviews

Volumn 21, Issue 2, 2016, Pages 137-155

  Goldenthal, Michael J ^a  

^a DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

Author keywords

Apoptosis; Autophagy; Mitochondria; Necrosis; Permeability; Pore

Indexed keywords

ADENOSINE; ALPHA TOCOPHEROL; APOPTOSIS INDUCING FACTOR; ASCORBIC ACID; BEPRIDIL; CARNITINE; CASPASE; CASPASE 3; CASPASE 7; CYTOCHROME C; DIAZOXIDE; ELAMIPRETIDE; ENDONUCLEASE G; HEXOKINASE; ISOFLURANE; NICORANDIL; NICOTINAMIDE ADENINE DINUCLEOTIDE; PROCASPASE 9; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN BNIP3; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATE SYNTHASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; SECOND MITOCHONDRIAL ACTIVATOR OF CASPASE; THIOCTIC ACID; UBIDECARENONE; VOLTAGE DEPENDENT ANION CHANNEL; CARRIER PROTEIN; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; REACTIVE OXYGEN METABOLITE;

APOPTOSIS; ARTICLE; AUTOPHAGY; BIOGENESIS; CALCIUM CELL LEVEL; CARDIOMYOPATHY; CELL AGING; CELL DEATH; CELL ENERGY; CELL SWELLING; CYTOSOL; DNA FRAGMENTATION; DNA FRAGMENTATION ASSAY; ENERGY METABOLISM; GENETIC ANALYSIS; HEART FAILURE; HEART MUSCLE CELL; HEART MUSCLE ISCHEMIA; HEART PROTECTION; HEART VENTRICLE REMODELING; HIGH THROUGHPUT SCREENING; HUMAN; MITOCHONDRIAL PERMEABILITY; MITOCHONDRION; OXIDATIVE STRESS; PROTEIN EXPRESSION; RESPIRATORY CHAIN; SIGNAL TRANSDUCTION; CARDIAC MUSCLE CELL; HEART MITOCHONDRION; METABOLISM; PATHOPHYSIOLOGY; RANDOMIZED CONTROLLED TRIAL (TOPIC);

CELL DEATH; ENERGY METABOLISM; HEART FAILURE; HUMANS; MITOCHONDRIA, HEART; MITOCHONDRIAL MEMBRANE TRANSPORT PROTEINS; MYOCYTES, CARDIAC; OXIDATIVE STRESS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; REACTIVE OXYGEN SPECIES;

EID: 84959321725     PISSN: 13824147     EISSN: 15737322     Source Type: Journal    
DOI: 10.1007/s10741-016-9531-1     Document Type: Article

References (216)

1. Leri A, Kajstura J, Anversa P (2011) Mechanisms of myocardial regeneration. Trends Cardiovasc Med 21:52–58
2. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN (2003) A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 111:1497–1504
3. 2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest 117:2431–2444
4. Mughal W, Dhingra R, Kirshenbaum LA (2012) Striking a balance: autophagy, apoptosis, and necrosis in a normal and failing heart. Curr Hypertens Rep 14:540–547
5. Gottlieb RA, Mentzer RM Jr (2013) Autophagy: an affair of the heart. Heart Fail Rev 18:575–584
6. Green DR, Galluzzi L, Kroemer G (2014) Cell biology. Metabolic control of cell death. Science 345:1250256
7. Konstantinidis K, Whelan RS, Kitsis RN (2012) Mechanisms of cell death in heart disease. Arterioscler Thromb Vasc Biol 32:1552–1562
8. Karch J, Kwong JQ, Burr AR, Sargent MA, Elrod JW, Peixoto PM, Martinez-Caballero S, Osinska H, Cheng EH, Robbins J, Kinnally KW, Molkentin JD (2013) Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice. Elife 2:e00772
9. Andres AM, Stotland A, Queliconi BB, Gottlieb RA (2015) A time to reap, a time to sow: mitophagy and biogenesis in cardiac pathophysiology. J Mol Cell Cardiol 78:62–72
10. Orogo AM, Gustafsson ÅB (2013) Cell death in the myocardium: my heart won’t go on. IUBMB Life 65:651–656
11. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308
12. Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D, Tsien RY, Lenardo MJ (2000) Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288:2354–2357
13. Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D (1995) A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270:7795–7798
14. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588
15. Boldin MP, Goncharov TM, Goltsev YV, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85:803–815
16. Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM (1998) An induced proximity model for caspase-8 activation. J Biol Chem 273:2926–2930
17. Stennicke HR, Jurgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D, Green DR, Reed JC, Froelich CJ, Salvesen GS (1998) Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem 273:27084–27090
18. Kushnareva Y, Newmeyer DD (2010) Bioenergetics and cell death. Ann NY Acad Sci 1201:50–57
19. Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99
20. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446
21. Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW (2002) Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 9:423–432
22. Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147–157
23. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219
24. Tait SW, Green DR (2013) Mitochondrial regulation of cell death. Cold Spring Harb Perspect Biol. 5 pii: a008706
25. Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Changs BS, Thompson CB, Wong S, Ng S, Fesik SW (1996) X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature (London) 381:335–341
26. Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R, Martinou JC (1997) Inhibition of Bax channel-forming activity by Bcl-2. Science 277:370–372
27. Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou J (2000) Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 345:271–278
28. Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164
29. Kushnareva Y, Andreyev AY, Kuwana T, Newmeyer DD (2012) Bax activation initiates the assembly of a multimeric catalyst that facilitates Bax pore formation in mitochondrial outer membranes. PLoS Biol 10:e1001394
30. Basañez G, Soane L, Hardwick JM (2012) A new view of the lethal apoptotic pore. PLoS Biol 10:e1001399
31. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730
32. Raemy E, Martinou JC (2014) Involvement of cardiolipin in tBID-induced activation of BAX during apoptosis. Chem Phys Lipids 179:70–74
33. Danial NN (2008) BAD: undertaker by night, candyman by day. Oncogene 27(Suppl 1):S53–S70
34. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014
35. Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2:156–162
36. Lartigue L, Medina C, Schembri L, Chabert P, Zanese M, Tomasello F, Dalibart R, Thoraval D, Crouzet M, Ichas F, De Giorgi F (2008) An intracellular wave of cytochrome c propagates and precedes Bax redistribution during apoptosis. J Cell Sci 121:3515–3523
37. Bhola PD, Mattheyses AL, Simon SM (2009) Spatial and temporal dynamics of mitochondrial membrane permeability waves during apoptosis. Biophys J 97:2222–2231
38. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, Anversa P (1999) Myocyte death in the failing human heart is gender dependent. Circ Res 85:856–866
39. Henriquez M, Armisen R, Stutzin A, Quest AF (2008) Cell death by necrosis, a regulated way to go. Curr Mol Med 8:187–206
40. Savage MK, Reed DJ (1994) Oxidation of pyridine nucleotides and depletion of ATP and ADP during calcium- and inorganic phosphate-induced mitochondrial permeability transition. Biochem Biophys Res Commun 200:1615–1620
41. Crompton M, Costi A (1990) 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 266:33–39
42. Vercesi AE, Kowaltowski AJ, Grijalba MT, Meinicke AR, Castilho RF (1997) The role of reactive oxygen species in mitochondrial permeability transition. Biosci Rep 7:43–52
43. Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177–196
44. 2+ transport. Biochim Biophys Acta 935:87–102
45. Di Lisa F, Bernardi P (1998) Mitochondrial function as a determinant of recovery or death in cell response to injury. Mol Cell Biochem 184:379–391
46. 2+-independent degradation of mitochondrial phospholipids. Biochemistry 41:7771–7780
47. Pepe S (2000) Mitochondrial function in ischaemia and reperfusion of the ageing heart. Clin Exp Pharmacol Physiol 27:745–750
48. 2+ induced membrane transition in mitochondria. II. Nature of the Ca 2þ trigger site. Arch Biochem Biophys 195:460–467
49. 2+-overload. Eur J Biochem 178:489–501
50. 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 274:611–614
51. Connern CP, Halestrap AP (1994) Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel. Biochem J 302:321–324
52. Griffiths EJ, Halestrap AP (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 307:93–98
53. 2+ release. Arch Biochem Biophys 195:468–477
54. 2+-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 268:153–160
55. Brustovetsky N, Becker A, Klingenberg M, Bamberg E (1996) Electrical currents associated with nucleotide transport by the reconstituted mitochondrial ADP/ATP carrier. Proc Natl Acad Sci USA 93:664–668
56. Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777:946–995
57. Chen C, Ko Y, Delannoy M, Ludtke SJ, Chiu W, Pedersen PL (2004) Mitochondrial ATP synthasome: three-dimensional structure by electron microscopy of the ATP synthase in complex formation with carriers for pi and ADP/ATP. J Biol Chem 279:31761–33176
58. 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 330:201–205
59. Szabo I, De Pinto V, Zoratti M (1993) The mitochondrial permeability transition pore may comprise VDAC molecules. II. The electrophysiological properties of VDAC are compatible with those of the mitochondrial megachannel. FEBS Lett 330:206–210
60. Pasdois P, Parker JE, Griffiths EJ, Halestrap AP (2013) Hexokinase II and reperfusion injury: TAT-HK2 peptide impairs vascular function in Langendorff-perfused rat hearts. Circ Res 112:e3–e7
61. Beutner G, Ruck A, Riede B, Brdiczka D (1998) Complexes between porin, hexokinase, mitochondrial creatine kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases. Biochim Biophys Acta 1368:7–18
62. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465
63. 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 9:550–555
64. − mitochondria. Biochim Biophys Acta 1757:590–595
65. Sileikyte J, Blachly-Dyson E, Sewell R, Carpi A, Menabo R, Di Lisa F, Ricchelli F, Bernardi P, Forte M (2014) Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (TSPO). J Biol Chem 289:13769–13781
66. Herick K, Krämer R, Lühring H (1997) Patch clamp investigation into the phosphate carrier from Saccharomyces cerevisiae mitochondria. Biochim Biophys Acta 1321:207–220
67. Kwong JQ, Davis J, Baines CP, Sargent MA, Karch J, Wang X (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209–1217
68. Gutiérrez-Aguilar M, Douglas DL, Gibson AK, Domeier TL, Molkentin JD, Baines CP (2014) Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. J Mol Cell Cardiol 72:316–325
69. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662
70. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280:18558–18561
71. Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA 102:12005–12010
72. Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P (2010) Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci USA 107:726–731
73. Nguyen TT, Stevens MV, Kohr M, Steenbergen C, Sack MN, Murphy E (2011) Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore. J Biol Chem 286:40184–40189
74. Eliseev RA, Malecki J, Lester T, Zhang Y, Humphrey J, Gunter TE (2009) Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect. J Biol Chem 284:9692–9699
75. Giorgio V, Bisetto E, Soriano ME, Dabbeni-Sala F, Basso E, Petronilli V, Forte MA, Bernardi P, Lippe G (2009) Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988
76. Antoniel M, Giorgio V, Fogolari F, Glick GD, Bernardi P, Lippe G (2014) The oligomycin-sensitivity conferring protein of mitochondrial ATP synthase: emerging new roles in mitochondrial pathophysiology. Int J Mol Sci 15:7513–7536
77. Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabó I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892
78. Bonora M, Bononi A, DeMarchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683
79. Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA, Licznerski P, Li H, Nabili P, Hockensmith K, Graham M, Porter GA Jr, Jonas EA (2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci USA 111:10580–10585
80. Carraro M, Giorgio V, Šileikytė J, Sartori G, Forte M, Lippe G, Zoratti M, Szabò I, Bernardi P (2014) Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition. J Biol Chem 289:15980–15985
81. Azarashvili TS, Tyynelä J, Odinokova IV, Grigorjev PA, Baumann M, Evtodienko YV, Saris NE (2002) Phosphorylation of a peptide related to subunit c of the F0F1-ATPase/ATP synthase and relationship to permeability transition pore opening in mitochondria. J Bioenerg Biomembr 34:279–284
82. Jonas EA, Porter GA Jr, Beutner G, Mnatsakanyan N, Alavian KN (2015) Cell death disguised: the mitochondrial permeability transition pore as the c-subunit of the F(1)F(O) ATP synthase. Pharmacol Res 99:382–392
83. Bonora M, Wieckowski MR, Chinopoulos C, Kepp O, Kroemer G, Galluzzi L, Pinton P (2015) Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 34:1475–1486
84. Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46:821–831
85. Halestrap AP (2014) The C ring of the F1Fo ATP synthase forms the mitochondrial permeability transition pore: a critical appraisal. Front Oncol 4:234
86. Bernardi P, Di Lisa F, Fogolari F, Lippe G (2015) From ATP to PTP and back: a dual function for the mitochondrial ATP synthase. Circ Res 116:1850–1862
87. Bernardi P (2013) The mitochondrial permeability transition pore: a mystery solved? Front Physiol 4:95
88. Bernardi P, Krauskopf A, Basso E, Petronilli V, Blachly-Dyson E, Di Lisa F, Forte MA (2006) The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 273:2077–2099
89. Fontaine E, Eriksson O, Ichas F, Bernardi P (1998) Regulation of the permeability transition pore in skeletal muscle mitochondria. Modulation by electron flow through the respiratory chain complex I. J Biol Chem 273:12662–12668
90. Sileikyte J, Petronilli V, Zulian A, Dabbeni-Sala F, Tognon G, Nikolov P, Bernardi P, Ricchelli F (2011) Regulation of the inner membrane mitochondrial permeability transition by the outer membrane translocator protein (peripheral benzodiazepine receptor). J Biol Chem 286:1046–1053
91. Ricchelli F, Šileikyte J, Bernardi P (2011) Shedding light on the mitochondrial permeability transition. Biochim Biophys Acta 1807:482–490
92. Lê-Quôc K, Lê-Quôc D (1985) Crucial role of sulfhydryl groups in the mitochondrial inner membrane structure. J Biol Chem 260:7422–7428
93. Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci USA 95:14681–14686
94. Marzo I, Brenner C, Zamzami N, Jürgensmeier JM, Susin SA, Vieira HL, Prévost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031
95. Whelan RS, Konstantinidis K, Wei AC, Chen Y, Reyna DE, Jha S, Yang Y, Calvert JW, Lindsten T, Thompson CB, Crow MT, Gavathiotis E, Dorn GW II, O’Rourke B, Kitsis RN (2012) Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci USA 109:6566–6571
96. 2+-dependent cell survival and death. Mol Cell 33:377–388
97. Brenner C, Cadiou H, Vieira HL, Zamzami N, Marzo I, Xie Z et al (2000) Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene 19:329–336
98. Arbel N, Ben-Hail D, Shoshan-Barmatz V (2012) Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem 287:23152–23161
99. Alavian KN, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli SM, Mariggio MA, Rahner C, McNay E, Shore GC, Smith PJ, Hardwick JM, Jonas EA (2011) Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1 FO ATP synthase. Nat Cell Biol 13:1224–1233
100. Chen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM, Cheng WC, Qi B, Li H, Alavian KN, Dayhoff-Brannigan M, Zou S, Pineda FJ, O’Rourke B, Ko YH, Pedersen PL, Kaczmarek LK, Jonas EA, Hardwick JM (2011) Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195:263–276
101. Halestrap AP, Pereira GC, Pasdois P (2015) The role of hexokinase in cardioprotection—mechanism and potential for translation. Br J Pharmacol 172:2085–2100
102. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658
103. Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627–637
104. Goldstein JC, Muñoz-Pinedo C, Ricci JE, Adams SR, Kelekar A, Schuler M, Tsien RY, Green DR (2005) Cytochrome c is released in a single step during apoptosis. Cell Death Differ 12:453–462
105. Waterhouse NJ, Goldstein JC, von Ahsen O, Schuler M, Newmeyer DD, Green DR (2001) Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol 153:319–328
106. Polster BM, Kinnally KW, Fiskum G (2001) BH3 death domain peptide induces cell type-selective mitochondrial outer membrane permeability. J Biol Chem 276:37887–37894
107. von Ahsen O, Renken C, Perkins G, Kluck RM, Bossy-Wetzel E, Newmeyer DD (2000) Preservation of mitochondrial structure and function after Bid- or Bax-mediated cytochrome c release. J Cell Biol 150:1027–1036
108. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189
109. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141
110. Saraste A, Pulkki K, Kallajoki M, Heikkila P, Laine P, Mattila S, Nieminen MS, Parvinen M, Voipio-Pulkki LM (1999) Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur J Clin Invest 29:380–386
111. Park M, Shen YT, Gaussin V, Heyndrickx GR, Bartunek J, Resuello RR, Natividad FF, Kitsis RN, Vatner DE, Vatner SF (2009) Apoptosis predominates in nonmyocytes in heart failure. Am J Physiol Heart Circ Physiol 297:H785–H791
112. Takemura G, Kanoh M, Minatoguchi S, Fujiwara H (2013) Cardiomyocyte apoptosis in the failing heart—a critical review from definition and classification of cell death. Int J Cardiol 167:2373–2386
113. Dorn GW II (2013) Molecular mechanisms that differentiate apoptosis from programmed necrosis. Toxicol Pathol 41:227–234
114. Gomes LC, Scorrano L (2013) Mitochondrial morphology in mitophagy and macroautophagy. Biochim Biophys Acta 1833:205–212
115. Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4:600–606
116. Dorn GW II (2010) Mitochondrial pruning by Nix and BNip3: an essential function for cardiac expressed death factors. J Cardiovasc Transl Res 3:374–383
117. Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG, Li H, Kirshenbaum LA, Hahn HS, Robbins J, Jones WK, Dorn GW (2007) Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117:2825–2833
118. Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klövekorn WP, Schaper J (2003) Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92:715–724
119. Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM (2001) Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 51:304–312
120. Yamamoto S, Sawada K, Shimomura H, Kawamura K, James TN (2000) On the nature of cell death during remodeling of hypertrophied human myocardium. J Mol Cell Cardiol 32:161–175
121. Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J (2003) Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 107:984–991
122. Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, Yang G, Matsui Y, Sadoshima J, Vatner SF (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci USA 102:13807–13812
123. Miyata S, Takemura G, Kawase Y, Li Y, Okada H, Maruyama R, Ushikoshi H, Esaki M, Kanamori H, Li L, Misao Y, Tezuka A, Toyo-Oka T, Minatoguchi S, Fujiwara T, Fujiwara H (2006) Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor. Am J Pathol 168:386–397
124. Nishida K, Yamaguchi O, Otsu K (2015) Degradation systems in heart failure. J Mol Cell Cardiol 84:212–222
125. Rothermel BA, Hill JA (2008) Autophagy in load-induced heart disease. Circ Res 103:1363–1369
126. Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12:831–835
127. Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38
128. Mihaylova MM, Shaw R (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023
129. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461
130. Huang C, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA (2011) Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS ONE 6:e20975
131. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (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 100:914–922
132. Biala AK, Kirshenbaum LA (2014) The interplay between cell death signaling pathways in the heart. Trends Cardiovasc Med 24:325–331
133. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, KarbowskiM YouleRJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380
134. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446
135. Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12:2245–2256
136. Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409–5420
137. MacVicar TD, Lane JD (2014) Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation. J Cell Sci 127:2313–2325
138. Kaser M, Kambacheld M, Kisters-Woike B, Langer T (2003) Oma1, a novel membrane bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease. J Biol Chem 278:46414–46423
139. McBride H, Soubannier V (2010) Mitochondrial function: OMA1 and OPA1, the grandmasters of mitochondrial health. Curr Biol 20:R274–R276
140. Shirihai OS, Song M, Dorn GW II (2015) How mitochondrial dynamism orchestrates mitophagy. Circ Res 116:1835–1849
141. Ikeda Y, Shirakabe A, Brady C, Zablocki D, Ohishi M, Sadoshima J (2015) Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system. J Mol Cell Cardiol 78:116–122
142. Stotland A, Gottlieb RA (2015) Mitochondrial quality control: easy come, easy go. Biochim Biophys Acta 1853:2802–2811
143. Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140–1151
144. Rosca MG, Hoppel CL (2013) Mitochondrial dysfunction in heart failure. Heart Fail Rev 18:607–622
145. Ventura-Clapier R, Garnier A, Veksler V, Joubert F (2011) Bioenergetics of the failing heart. Biochim Biophys Acta 1813:1360–1372
146. Marin-Garcia J, Goldenthal MJ (2008) Mitochondrial centrality in heart failure. Heart Fail Rev 13:137–150
147. Ping P, Gustafsson ÅB, Bers DM, Blatter LA, Cai H, Jahangir A, Kelly D, Muoio D, O’Rourke B, Rabinovitch P, Trayanova N, Van Eyk J, Weiss JN, Wong R, Schwartz Longacre L (2015) Harnessing the power of integrated mitochondrial biology and physiology: a special report on the NHLBI mitochondria in heart diseases initiative. Circ Res 117:234–238
148. Lai L, Leone TC, Keller MP, Martin OJ, Broman AT, Nigro J, Kapoor K, Koves TR, Stevens R, Ilkayeva OR, Vega RB, Attie AD, Muoio DM, Kelly DP (2014) Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ Heart Fail 7:1022–1031
149. Vega RB, Horton JL, Kelly DP (2015) Maintaining ancient organelles: mitochondrial biogenesis and maturation. Circ Res 116:1820–1834
150. Nickel A, Löffler J, Maack C (2013) Myocardial energetics in heart failure. Basic Res Cardiol 108:358
151. Carley AN, Taegtmeyer H, Lewandowski ED (2014) Mechanisms linking energy substrate metabolism to the function of the heart. Circ Res 114:717–729
152. Taegtmeyer H, Lubrano G (2014) Rethinking cardiac metabolism: metabolic cycles to refuel and rebuild the failing heart. F1000Prime Rep 6:90
153. O’Rourke B, Van Eyk JE, Foster DB (2011) Mitochondrial protein phosphorylation as a regulatory modality: implications for mitochondrial dysfunction in heart failure. Congest Heart Fail 17:269–282
154. Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, Samant S, Ravindra PV, Isbatan A, Gupta MP (2010) Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem 285:3133–3144
155. Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz SC Jr, Suthammarak W, Gong G, Sedensky MM, Morgan PG, Wang W, Tian R (2013) Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 18:239–250
156. Chipuk JE, Bouchier-Hayes L, Green DR (2006) Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396–1402
157. Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G (2012) Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep 13:322–330
158. Li K, Li Y, Shelton JM, Richardson JA, Spencer E, Chen ZJ, Wang X, Williams RS (2000) Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101:389–399
159. Brown D, Yu BD, Joza N, Benit P, Meneses J, Firpo M, Rustin P, Penninger JM, Martin GR (2006) Loss of AIF function causes cell death in the mouse embryo, but the temporal progression of patterning is normal. Proc Natl Acad Sci USA 103:9918–9923
160. Vahsen N, Candé C, Brière JJ, Bénit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schägger H, Rustin P, Kroemer G (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689
161. Joza N, Oudit GY, Brown D, Bénit P, Kassiri Z, Vahsen N, Benoit L, Patel MM, Nowikovsky K, Vassault A, Backx PH, Wada T, Kroemer G, Rustin P, Penninger JM (2005) Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy and dilated cardiomyopathy. Mol Cell Biol 25:10261–10272
162. Cheung C, Joza N, Steenaart NA, McClellan KA, Neuspiel M, McNamara S, MacLaurin JG, Rippstein P, Park DS, Shore GC, McBride HM, Penninger JM, Slack RS (2006) Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis. EMBO J 25:4061–4073
163. Zick M, Rabl R, Reichert AS (2009) Cristae formation-linking ultrastructure and function of mitochondria. Biochim Biophys Acta 1793:5–19
164. Davies KM, Strauss M, Daum B, Kief JH, Osiewacz HD, Rycovska A, Zickermann V, Kuhlbrandt W (2011) Macromolecular organization of ATP synthase and complex I in whole mitochondria. Proc Natl Acad Sci USA 108:14121–14126
165. Giraud MF, Paumard P, Soubannier V, Vaillier J, Arselin G, Salin B, Schaeffer J, Brethes D, di Rago JP, Velours J (2002) Is there a relationship between the supramolecular organization of the mitochondrial ATP synthase and formation of cristae? Biochim Biophys Acta 1555:174–182
166. Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, Mueller DM, Brethes D, di Rago JP, Velours J (2002) The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 21:221–230
167. Habersetzer J, Larrieu I, Priault M, Salin B, Rossignol R, Brèthes D, Paumard P (2013) Human F1F0 ATP synthase, mitochondrial ultrastructure and OXPHOS impairment: a (super-) complex matter? PLoS ONE 8:e75429
168. Williams GS, Boyman L, Lederer WJ (2015) Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol 78:35–45
169. Finkel T, Menazza S, Holmström KM, Parks RJ, Liu J, Sun J, Liu J, Pan X, Murphy E (2015) The ins and outs of mitochondrial calcium. Circ Res 116:1810–1819
170. Long Q, Yang K, Yang Q (2015) Regulation of mitochondrial ATP synthase in cardiac pathophysiology Am J. Cardiovasc Dis 5:19–32
171. Bernardi P, Rasola A, Forte M, Lippe G (2015) The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol Rev 95:1111–1155
172. Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249
173. Wong R, Steenbergen C, Murphy E (2012) Mitochondrial permeability transition pore and calcium handling. Methods Mol Biol 810:235–242
174. Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R, Wieckowski MR, Campo G, Pinton P (2015) Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. J Mol Cell Cardiol 78:142–153
175. Weiss JN, Korge P, Honda HM, Ping P (2003) Role of the mitochondrial permeability transition in myocardial disease. Circ Res 93:292–301
176. De Stefani DD, Raffaello A, Teardo E, Szabò I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340
177. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345
178. Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, Fergusson MM, Rovira II, Allen M, Springer DA, Aponte AM, Gucek M, Balaban RS, Murphy E, Finkel T (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 15:1464–1472
179. 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 56:1–13
180. Garrido-Maraver J, Cordero MD, Oropesa-Avila M, Vega AF, de la Mata M, Pavon AD, Alcocer-Gomez E, Calero CP, Paz MV, Alanis M, de Lavera I, Cotan D, Sanchez-Alcazar JA (2014) Clinical applications of coenzyme Q10. Front Biosci 19:619–633
181. Ajith TA, Jayakumar T (2014) Mitochondria-targeted agents: future perspectives of mitochondrial pharmaceutics in cardiovascular diseases. World J Cardiol 6:1091–1099
182. Yang YK, Wang LP, Chen L, Yao XP, Yang KQ, Gao LG, Zhou XL (2015) Coenzyme Q10 treatment of cardiovascular disorders of ageing including heart failure, hypertension and endothelial dysfunction. Clin Chim Acta 450:83–89
183. DiNicolantonio JJ, Bhutani J, McCarty MF, O’Keefe JH (2015) Coenzyme Q10 for the treatment of heart failure: a review of the literature. Open Heart 2(1):e000326
184. Madmani ME, Yusuf Solaiman A, Tamr Agha K, Madmani Y, Shahrour Y, Essali A, Kadro W (2014) Coenzyme Q10 for heart failure. Cochrane Database Syst Rev 6:CD008684
185. Mortensen SA, Rosenfeldt F, Kumar A, Dolliner P, Filipiak KJ, Pella D, Alehagen U, Steurer G, Littarru GP (2014) Q-SYMBIO study investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail 2:641–649
186. Rizos I (2000) Three-year survival of patients with heart failure caused by dilated cardiomyopathy and l-carnitine administration. Am Heart J 139:S120–S123
187. Serati AR, Motamedi MR, Emami S, Varedi P, Movahed MR (2010) l-carnitine treatment in patients with mild diastolic heart failure is associated with improvement in diastolic function and symptoms. Cardiology 116:178–182
188. Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM (2009) A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 11:414–430
189. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2:CD007176
190. Cochemé HM, Murphy MP (2010) Can antioxidants be effective therapeutics? Curr Opin Investig Drugs 11:426–431
191. Murphy MP, Smith RA (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629–656
192. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276:4588–4596
193. Smith RA, Porteous CM, Gane AM, Murphy MP (2003) Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci USA 100:5407–5412
194. Oyewole AO, Birch-Machin MA (2015) Mitochondria-targeted antioxidants. FASEB J 29:4766–4771
195. Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cochemé HM, Murphy MP, Dominiczak AF (2009) Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 54:322–328
196. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA (2005) Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 19:1088–1095
197. Smith RA, Murphy MP (2010) Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann NY Acad Sci 1201:96–103
198. Szeto HH, Birk AV (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther 96:672–683
199. Javadov S, Karmazyn M, Escobales N (2009) Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J Pharmacol Exp Ther 330:670–678
200. Sileikyte J, Roy S, Porubsky P, Neuenswander B, Wang J, Hedrick M, Pinkerton AB, Salaniwal S, Kung P, Mangravita-Novo A, Smith LH, Bourdette DN, Jackson MR, Aubé J, Chung TDY, Schoenen FJ, Forte MA, Bernardi P (2010) Small molecules targeting the mitochondrial permeability transition. Probe Reports from the NIH Molecular Libraries Program [Internet]. National Center for Biotechnology Information (US), Bethesda
201. Arakawa S, Nakanomyo I, Kudo-Sakamoto Y, Akazawa H, Komuro I, Shimizu S (2015) Identification of a novel compound that inhibits both mitochondria-mediated necrosis and apoptosis. Biochem Biophys Res Commun 467:1006–1011
202. 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–H502
203. Javadov SA, Lim KH, Kerr PM, Suleiman MS, Angelini GD, Halestrap AP (2000) Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res 45:360–369
204. Rajesh KG, Sasaguri S, Suzuki R, Maeda H (2003) Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression. Am J Physiol Heart Circ Physiol 285:H2171–H2178
205. Lim SY, Davidson SM, Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovasc Res 75:530–535
206. 2+-induced mitochondrial permeability transition. Cardiovasc Res 61:115–122
207. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM (2002) Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial pre-conditioning? Cardiovasc Res 55:534–543
208. Dongworth RK, Hall AR, Burke N, Hausenloy DJ (2014) Targeting mitochondria for cardioprotection: examining the benefit for patients. Future Cardiol 10:255–272
209. Mio Y, Uezono S, Kitahata H (2014) Anesthetic cardioprotection in relation to mitochondria: basic science. Curr Pharm Des 20:5673–5680
210. Coetzee WA (2013) Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol Ther 140:167–175
211. Akao M, Teshima Y, Marbán E (2002) Antiapoptotic effect of nicorandil mediated by mitochondrial ATP-sensitive potassium channels in cultured cardiac myocytes. J Am Coll Cardiol 21:803–810
212. IONA Study Group (2002) Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 359:1269–1275
213. Zhao F, Chaugai S, Chen P, Wang Y, Wang DW (2014) Effect of nicorandil in patients with heart failure: a systematic review and meta-analysis. Cardiovasc Ther 32:283–296
214. Kasama S, Toyama T, Iwasaki T, Sumino H, Kumakura H, Minami K, Ichikawa S, Matsumoto N, Sato Y, Kurabayashi M (2014) Effects of oral nicorandil therapy on sympathetic nerve activity and cardiac events in patients with chronic heart failure: subanalysis of our previous report using propensity score matching. Eur J Nucl Med Mol Imaging 41:144–154
215. Ishihara S, Koga T, Kaseda S, Nyuta E, Haga Y, Fujishima S, Ishitsuka T, Sadoshima S (2012) Effects of intravenous nicorandil on the mid-term prognosis of patients with acute heart failure syndrome. Circ J 76:1169–1176
216. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke EH, Bazan NG, Bertrand MJ, Bianchi K et al (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22:58–73