Journal of Bioenergetics and Biomembranes

, Volume 49, Issue 1, pp 13–25 | Cite as

Physiological roles of the mitochondrial permeability transition pore

  • Nelli Mnatsakanyan
  • Gisela Beutner
  • George A. Porter
  • Kambiz N. Alavian
  • Elizabeth A. Jonas


Neurons experience high metabolic demand during such processes as synaptic vesicle recycling, membrane potential maintenance and Ca2+ exchange/extrusion. The energy needs of these events are met in large part by mitochondrial production of ATP through the process of oxidative phosphorylation. The job of ATP production by the mitochondria is performed by the F1FO ATP synthase, a multi-protein enzyme that contains a membrane-inserted portion, an extra-membranous enzymatic portion and an extensive regulatory complex. Although required for ATP production by mitochondria, recent findings have confirmed that the membrane-confined portion of the c-subunit of the ATP synthase also houses a large conductance uncoupling channel, the mitochondrial permeability transition pore (mPTP), the persistent opening of which produces osmotic dysregulation of the inner mitochondrial membrane, uncoupling of oxidative phosphorylation and cell death. Recent advances in understanding the molecular components of mPTP and its regulatory mechanisms have determined that decreased uncoupling occurs in states of enhanced mitochondrial efficiency; relative closure of mPTP therefore contributes to cellular functions as diverse as cardiac development and synaptic efficacy.


Mitochondria Permeability transition pore Synaptic transmission Synaptic plasticity ATP synthase 


  1. Abramov AY, Fraley C, Diao CT, Winkfein R, Colicos MA, Duchen MR, French RJ, Pavlov E (2007) Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. Proc Natl Acad Sci U S A 104:18091–18096. doi: 10.1073/pnas.0708959104 CrossRefGoogle Scholar
  2. Adams JM, Cory S (2007) The bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337CrossRefGoogle Scholar
  3. 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 F1FO ATP synthase. Nat Cell Biol 13:1224–1233. doi: 10.1038/ncb2330) CrossRefGoogle Scholar
  4. 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 U S A 111:10580–10585. doi: 10.1073/pnas.1401591111
  5. Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC (2000) Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 345(Pt 2):271–278CrossRefGoogle Scholar
  6. Azarashvili T, Odinokova I, Bakunts A, Ternovsky V, Krestinina O, Tyynela J, Saris NE (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 55:69–77. doi: 10.1016/j.ceca.2013.12.002 CrossRefGoogle Scholar
  7. M. F. Beal, Mitochondria and neurodegeneration. Novartis Found Symp 287, 183–192; discussion 192–186 (2007).Google Scholar
  8. Berman SB, Chen YB, Qi B, McCaffery JM, Rucker EB 3rd, Goebbels S, Nave KA, Arnold BA, Jonas EA, Pineda FJ, Hardwick JM (2009) published online EpubMar 9 Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 184:707–719CrossRefGoogle Scholar
  9. Bernardi P (1999) Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79:1127–1155Google Scholar
  10. Beutner G, Ruck A, Riede B, Welte W, Brdiczka D (1996) published online EpubNov 4 Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore. FEBS Lett 396:189–195CrossRefGoogle Scholar
  11. Beutner G, Ruck A, Riede B, Brdiczka D (1998) published online EpubJan 5 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 1368:7–18CrossRefGoogle Scholar
  12. Beutner G, Eliseev RA, Porter GA Jr (2014) Initiation of electron transport chain activity in the embryonic heart coincides with the activation of mitochondrial complex 1 and the formation of supercomplexes. PLoS One 9:e113330. doi: 10.1371/journal.pone.0113330)
  13. Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683. doi: 10.4161/cc.23599 CrossRefGoogle Scholar
  14. Bonora M, Wieckowski MR, Chinopoulos C, Kepp O, Kroemer G, Galluzzi L, Pinton P (2014) Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 0. doi: 10.1038/onc.2014.96
  15. Borjesson SI, Elinder F (2008) Structure, function, and modification of the voltage sensor in voltage-gated ion channels. Cell Biochem Biophys 52:149–174. doi: 10.1007/s12013-008-9032-5) CrossRefGoogle Scholar
  16. Brand MD (2005) published online EpubNov The efficiency and plasticity of mitochondrial energy transduction. Biochem Soc Trans 33:897–904CrossRefGoogle Scholar
  17. Carbajo RJ, Kellas FA, Runswick MJ, Montgomery MG, Walker JE, Neuhaus D (2005) Structure of the F1-binding domain of the stator of bovine F1Fo-ATPase and how it binds an alpha-subunit. J Mol Biol 351:824–838. doi: 10.1016/j.jmb.2005.06.012 CrossRefGoogle Scholar
  18. Chen C, Ko Y, Delannoy M, Ludtke SJ, Chiu W, Pedersen PL (2004) published online EpubJul 23 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 279:31761–31768CrossRefGoogle Scholar
  19. 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) published online EpubOct 17 Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195:263–276CrossRefGoogle Scholar
  20. Chinopoulos C, Szabadkai G (2014) What Makes You Can also Break You, Part III: Mitochondrial Permeability Transition Pore Formation by an Uncoupling Channel within the C-Subunit Ring of the F1FO ATP Synthase? Frontiers oncol 4:235. doi: 10.3389/fonc.2014.00235) CrossRefGoogle Scholar
  21. Cho SW, Park JS, Heo HJ, Park SW, Song S, Kim I, Han YM, Yamashita JK, Youm JB, Han J, Koh GY (2014) Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells. J Am Heart Assoc 3:e000693. doi: 10.1161/JAHA.113.000693 CrossRefGoogle Scholar
  22. Chouhan AK, Ivannikov MV, Lu Z, Sugimori M, Llinas RR, Macleod GT (2012) Cytosolic calcium coordinates mitochondrial energy metabolism with presynaptic activity. J Neurosci 32:1233–1243. doi: 10.1523/JNEUROSCI.1301-11.2012 CrossRefGoogle Scholar
  23. Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249CrossRefGoogle Scholar
  24. 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 258:729–735CrossRefGoogle Scholar
  25. Csordas G, Thomas AP, Hajnoczky G (2001) published online EpubOct Calcium signal transmission between ryanodine receptors and mitochondria in cardiac muscle. Trends cardiovasc med 11:269–275CrossRefGoogle Scholar
  26. 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. doi: 10.1016/j.ceca.2014.03.004 CrossRefGoogle Scholar
  27. Dejean LM, Martinez-Caballero S, Guo L, Hughes C, Teijido O, Ducret T, Ichas F, Korsmeyer SJ, Antonsson B, Jonas EA, Kinnally KW (2005) Oligomeric bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-induced channel. Mol Biol Cell 16:2424–2432CrossRefGoogle Scholar
  28. Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW (2006) Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. Biochim Biophys Acta 1762:191–201 published online EpubFebCrossRefGoogle Scholar
  29. Di Lisa F, Carpi A, Giorgio V, Bernardi P (2011) The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. Biochim Biophys Acta 1813:1316–1322. doi: 10.1016/j.bbamcr.2011.01.031 CrossRefGoogle Scholar
  30. Dodson MW, Guo M (2007) published online EpubJun Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease. Curr Opin Neurobiol 17:331–337CrossRefGoogle Scholar
  31. Elrod JW, Wong R, Mishra S, Vagnozzi RJ, Sakthievel B, Goonasekera SA, Karch J, Gabel S, Farber J, Force T, Brown JH, Murphy E, Molkentin JD (2010) Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J Clin Invest 120:3680–3687. doi: 10.1172/JCI43171 CrossRefGoogle Scholar
  32. Elustondo PA, Angelova PR, Kawalec M, Michalak M, Kurcok P, Abramov AY, Pavlov EV (2013) Polyhydroxybutyrate targets mammalian mitochondria and increases permeability of plasmalemmal and mitochondrial membranes. PLoS One 8:e75812. doi: 10.1371/journal.pone.0075812) CrossRefGoogle Scholar
  33. Friel DD, Tsien RW (1994) An FCCP-sensitive Ca2+ store in bullfrog sympathetic neurons and its participation in stimulus-evoked changes in [Ca2+]i. J Neurosci 14:4007–4024Google Scholar
  34. Fujiwara M, Yan P, Otsuji TG, Narazaki G, Uosaki H, Fukushima H, Kuwahara K, Harada M, Matsuda H, Matsuoka S, Okita K, Takahashi K, Nakagawa M, Ikeda T, Sakata R, Mummery CL, Nakatsuji N, Yamanaka S, Nakao K, Yamashita JK (2011) Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS One 6:e16734. doi: 10.1371/journal.pone.0016734) CrossRefGoogle Scholar
  35. Galonek HL, Hardwick JM (2006) Upgrading the BCL-2 network.[comment]. Nat Cell Biol 8:1317–1319CrossRefGoogle Scholar
  36. Giorgio V, Bisetto E, Soriano ME, Dabbeni-Sala F, Basso E, Petronilli V, Forte MA, Bernardi P, Lippe G (2009) published online EpubDec 4 Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988CrossRefGoogle Scholar
  37. Giorgio V, Soriano ME, Basso E, Bisetto E, Lippe G, Forte MA, Bernardi P (2010) published online EpubJun-Jul Cyclophilin D in mitochondrial pathophysiology. Biochim Biophys Acta 1797:1113–1118CrossRefGoogle Scholar
  38. Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabo I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110:5887–5892. doi: 10.1073/pnas.1217823110 CrossRefGoogle Scholar
  39. Gomez L, Thibault H, Gharib A, Dumont JM, Vuagniaux G, Scalfaro P, Derumeaux G, Ovize M (2007) Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol 293:H1654–H1661. doi: 10.1152/ajpheart.01378.2006 CrossRefGoogle Scholar
  40. Gottlieb E, Armour SM, Thompson CB (2002) Mitochondrial respiratory control is lost during growth factor deprivation. Proc Natl Acad Sci U S A 99:12801–12806CrossRefGoogle Scholar
  41. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629CrossRefGoogle Scholar
  42. Griffiths EJ, Halestrap AP (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 307(Pt 1):93–98 published online EpubApr 1CrossRefGoogle Scholar
  43. Guerrieri F, Capozza G, Kalous M, Papa S (1992) published online EpubNov 30 Age-related changes of mitochondrial F0F1 ATP synthase. Ann N Y Acad Sci 671:395–402CrossRefGoogle Scholar
  44. Gunter TE, Sheu SS (2009) Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim Biophys Acta 1787:1291–1308. doi: 10.1016/j.bbabio.2008.12.011 CrossRefGoogle Scholar
  45. Gutierrez-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. doi: 10.1016/j.yjmcc.2014.04.008 CrossRefGoogle Scholar
  46. Halestrap AP, Davidson AM (1990) published online EpubMay 15 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 268:153–160CrossRefGoogle Scholar
  47. Hausenloy D, Wynne A, Duchen M, Yellon D (2004) Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 109:1714–1717. doi: 10.1161/01.CIR.0000126294.81407.7D CrossRefGoogle Scholar
  48. R. A. Haworth, D. R. Hunter, The Ca2+−induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch Biochem Biophys 195, 460–467 (1979); published online EpubJulGoogle Scholar
  49. Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA (2008) published online EpubMar Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmission. J Neurophysiol 99:1515–1522CrossRefGoogle Scholar
  50. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) published online EpubNov 22 Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336CrossRefGoogle Scholar
  51. Holmstrom KM, Marina N, Baev AY, Wood NW, Gourine AV, Abramov AY (2013) Signalling properties of inorganic polyphosphate in the mammalian brain. Nat Commun 4:1362. doi: 10.1038/ncomms2364) CrossRefGoogle Scholar
  52. Hom JR, Quintanilla RA, Hoffman DL, de Mesy Bentley KL, Molkentin JD, Sheu SS, Porter GA Jr (2011) The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell 21:469–478. doi: 10.1016/j.devcel.2011.08.008
  53. Hubbard MJ, McHugh NJ (1996) published online EpubAug 12 Mitochondrial ATP synthase F1-beta-subunit is a calcium-binding protein. FEBS Lett 391:323–329CrossRefGoogle Scholar
  54. D. R. Hunter, R. A. Haworth, The Ca2+−induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195, 453–459 (1979); published online EpubJulGoogle Scholar
  55. Huser J, Blatter LA (1999) published online EpubOct 15 Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore. Biochem J 343(Pt 2):311–317CrossRefGoogle Scholar
  56. F. Ichas, J. P. Mazat, 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, 33–50 (1998); published online EpubAug 10Google Scholar
  57. Jonas E (2006) BCL-xL regulates synaptic plasticity. Mol Interv 6:208–222CrossRefGoogle Scholar
  58. Jonas EA (2009) published online EpubAug Molecular participants in mitochondrial cell death channel formation during neuronal ischemia. Exp Neurol 218:203–212CrossRefGoogle Scholar
  59. Jonas EA, Knox RJ, Kaczmarek LK (1997) Giga-ohm seals on intracellular membranes: a technique for studying intracellular ion channels in intact cells. Neuron 19:7–13CrossRefGoogle Scholar
  60. Jonas EA, Buchanan J, Kaczmarek LK (1999) Prolonged activation of mitochondrial conductances during synaptic transmission. Science 286:1347–1350CrossRefGoogle Scholar
  61. Jonas EA, Hoit D, Hickman JA, Brandt TA, Polster BM, Fannjiang Y, McCarthy E, Montanez MK, Hardwick JM, Kaczmarek LK (2003) Modulation of synaptic transmission by the BCL-2 family protein BCL-xL. J Neurosci 23:8423–8431Google Scholar
  62. Jonckheere AI, Smeitink JA, Rodenburg RJ (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35:211–225. doi: 10.1007/s10545-011-9382-9 CrossRefGoogle Scholar
  63. Jouaville LS, Ichas F, Mazat JP (1998) published online EpubJul Modulation of cell calcium signals by mitochondria. Mol Cell Biochem 184:371–376CrossRefGoogle Scholar
  64. Karch J, Molkentin JD (2014) Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 111:10396–10397. doi: 10.1073/pnas.1410104111 CrossRefGoogle Scholar
  65. Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH (2006) Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.[see comment]. Nat Cell Biol 8:1348–1358CrossRefGoogle Scholar
  66. Kinnally KW, Campo ML, Tedeschi H (1989) Mitochondrial channel activity studied by patch-clamping mitoplasts. J Bioenerg Biomembr 21:497–506CrossRefGoogle Scholar
  67. K. W. Kinnally, S. Martinez-Caballero, L. M. Dejean, (2006) Detection of the mitochondrial apoptosis-induced channel (MAC) and its regulation by Bcl-2 family proteins. Current protoc. toxicol. Chapter 2, Unit2 12; published online EpubDecGoogle Scholar
  68. Kinnally KW, Peixoto PM, Ryu SY, Dejean LM (2011) Is mPTP the gatekeeper for necrosis, apoptosis, or both? Biochim Biophys Acta 1813:616–622. doi: 10.1016/j.bbamcr.2010.09.013 CrossRefGoogle Scholar
  69. 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.[see comment]. Nature 427:461–465CrossRefGoogle Scholar
  70. Korge P, Yang L, Yang JH, Wang Y, Qu Z, Weiss JN (2011) Protective role of transient pore openings in calcium handling by cardiac mitochondria. J Biol Chem 286:34851–34857. doi: 10.1074/jbc.M111.239921 CrossRefGoogle Scholar
  71. Kowaltowski AJ, Naia-da-Silva ES, Castilho RF, Vercesi AE (1998) Ca2+−stimulated mitochondrial reactive oxygen species generation and permeability transition are inhibited by dibucaine or Mg2+. Arch Biochem Biophys 359:77–81. doi: 10.1006/abbi.1998.0870 CrossRefGoogle Scholar
  72. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD (2008) Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab 7:312–320. doi: 10.1016/j.cmet.2008.02.004 CrossRefGoogle Scholar
  73. Kwong JQ, Davis J, Baines CP, Sargent MA, Karch J, Wang X, Huang T, Molkentin JD (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209–1217. doi: 10.1038/cdd.2014.36 CrossRefGoogle Scholar
  74. Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777:946–952. doi: 10.1016/j.bbabio.2008.03.009 CrossRefGoogle Scholar
  75. Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R, McNay EC, Yu T, Schwarzenbacher R, Bossy B, Bossy-Wetzel E, Bennett MV, Pypaert M, Hickman JA, Smith PJ, Hardwick JM, Jonas EA (2008) Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 105:2169–2174CrossRefGoogle Scholar
  76. Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141:859–871 published online EpubMay 28CrossRefGoogle Scholar
  77. Li H, Alavian KN, Lazrove E, Mehta N, Jones A, Zhang P, Licznerski P, Graham M, Uo T, Guo J, Rahner C, Duman RS, Morrison RS, Jonas EA (2013) A bcl-xL-Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis. Nat Cell Biol 15:773–785. doi: 10.1038/ncb2791 CrossRefGoogle Scholar
  78. Lopreiato R, Giacomello M, Carafoli E (2014) The plasma membrane calcium pump: new ways to look at an old enzyme. J Biol Chem 289:10261–10268. doi: 10.1074/jbc.O114.555565 CrossRefGoogle Scholar
  79. Martinez-Caballero S, Dejean LM, Jonas EA, Kinnally KW (2005) The role of the mitochondrial apoptosis induced channel MAC in cytochrome c release. J Bioenerg Biomembr 37:155–164CrossRefGoogle Scholar
  80. Matthies D, Preiss L, Klyszejko AL, Muller DJ, Cook GM, Vonck J, Meier T (2009) The c13 ring from a thermoalkaliphilic ATP synthase reveals an extended diameter due to a special structural region. J Mol Biol 388:611–618. doi: 10.1016/j.jmb.2009.03.052 CrossRefGoogle Scholar
  81. McGeoch JE, Guidotti G (1997) published online EpubAug 22 A 0.1-700 Hz current through a voltage-clamped pore: candidate protein for initiator of neural oscillations. Brain Res 766:188–194CrossRefGoogle Scholar
  82. McGeoch JE, McGeoch MW (2008) Entrapment of water by subunit c of ATP synthase. J Royal Soc, Interface/ Roy Soc 5:311–318. doi: 10.1098/rsif.2007.1146
  83. McGeoch JE, McGeoch MW, Mao R, Guidotti G (2000) Opposing actions of cGMP and calcium on the conductance of the F(0) subunit c pore. Biochem Biophys Res Commun 274:835–840. doi: 10.1006/bbrc.2000.3231 CrossRefGoogle Scholar
  84. Meier T, Matthey U, Henzen F, Dimroth P, Muller DJ (2001) published online EpubSep 21 The central plug in the reconstituted undecameric c cylinder of a bacterial ATP synthase consists of phospholipids. FEBS Lett 505:353–356CrossRefGoogle Scholar
  85. Neher E, Sakaba T (2008) Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59:861–872. doi: 10.1016/j.neuron.2008.08.019 CrossRefGoogle Scholar
  86. Norris U, Karp PE, Fimmel AL (1992) published online EpubJul Mutational analysis of the glycine-rich region of the c subunit of the Escherichia coli F0F1 ATPase. J Bacteriol 174:4496–4499CrossRefGoogle Scholar
  87. Oberfeld B, Brunner J, Dimroth P (2006) Phospholipids occupy the internal lumen of the c ring of the ATP synthase of Escherichia coli. Biochemistry 45:1841–1851. doi: 10.1021/bi052304+ CrossRefGoogle Scholar
  88. Pasdois P, Parker JE, Halestrap AP (2013) Extent of mitochondrial hexokinase II dissociation during ischemia correlates with mitochondrial cytochrome c release, reactive oxygen species production, and infarct size on reperfusion. J Am Heart Assoc 2:e005645. doi: 10.1161/JAHA.112.005645 Google Scholar
  89. Pavlov EV, Priault M, Pietkiewicz D, Cheng EH, Antonsson B, Manon S, Korsmeyer SJ, Mannella CA, Kinnally KW (2001) A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and bax expression in yeast. J Cell Biol 155:725–731CrossRefGoogle Scholar
  90. Pavlov E, Zakharian E, Bladen C, Diao CT, Grimbly C, Reusch RN, French RJ (2005) A large, voltage-dependent channel, isolated from mitochondria by water-free chloroform extraction. Biophys J 88:2614–2625. doi: 10.1529/biophysj.104.057281 CrossRefGoogle Scholar
  91. Pedersen PL (1994) published online EpubDec 1 ATP synthase. The machine that makes ATP. Curr biol: CB 4:1138–1141CrossRefGoogle Scholar
  92. Pedersen PL, Hullihen J (1978) published online EpubApr 10 Adenosine triphosphatase of rat liver mitochondria. Capacity of the homogeneous F1 component of the enzyme to restore ATP synthesis in urea-treated membranes. J Biol Chem 253:2176–2183Google Scholar
  93. Petronilli V, Szabo I, Zoratti M (1989) The inner mitochondrial membrane contains ion-conducting channels similar to those found in bacteria. FEBS Lett 259:137–143CrossRefGoogle Scholar
  94. Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, Di Lisa F (1999) 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 76:725–734. doi: 10.1016/S0006-3495(99)77239-5) CrossRefGoogle Scholar
  95. Pogoryelov D, Reichen C, Klyszejko AL, Brunisholz R, Muller DJ, Dimroth P, Meier T (2007) The oligomeric state of c rings from cyanobacterial F-ATP synthases varies from 13 to 15. J Bacteriol 189:5895–5902. doi: 10.1128/JB.00581-07 CrossRefGoogle Scholar
  96. Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408. doi: 10.1152/physrev.00004.2005 CrossRefGoogle Scholar
  97. Rizzuto R, Bernardi P, Pozzan T (2000) published online EpubNov 15 Mitochondria as all-round players of the calcium game. J Physiol 529(Pt 1):37–47CrossRefGoogle Scholar
  98. Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P (2009) published online EpubNov Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 1787:1342–1351CrossRefGoogle Scholar
  99. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578. doi: 10.1038/nrm3412 CrossRefGoogle Scholar
  100. Roestenberg P, Manjeri GR, Valsecchi F, Smeitink JA, Willems PH, Koopman WJ (2012) Pharmacological targeting of mitochondrial complex I deficiency: the cellular level and beyond. Mitochondrion 12:57–65. doi: 10.1016/j.mito.2011.06.011 CrossRefGoogle Scholar
  101. Schneggenburger R, Neher E (2005) Presynaptic calcium and control of vesicle fusion. Curr Opin Neurobiol 15:266–274. doi: 10.1016/j.conb.2005.05.006 CrossRefGoogle Scholar
  102. Seidlmayer LK, Blatter LA, Pavlov E, Dedkova EN (2012) Inorganic polyphosphate–an unusual suspect of the mitochondrial permeability transition mystery. Channels 6:463–467. doi: 10.4161/chan.21939 CrossRefGoogle Scholar
  103. Sorgato MC, Keller BU, Stuhmer W (1987) Patch-clamping of the inner mitochondrial membrane reveals a voltage-dependent ion channel. Nature 330:498–500CrossRefGoogle Scholar
  104. Stotz SC, Scott LO, Drummond-Main C, Avchalumov Y, Girotto F, Davidsen J, Gomez-Garcia MR, Rho JM, Pavlov EV, Colicos MA (2014) Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels. Mol brain 7:42. doi: 10.1186/1756-6606-7-42 CrossRefGoogle Scholar
  105. Szabo I, Zoratti M (1991) The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 266:3376–3379Google Scholar
  106. Szabo I, Bernardi P, Zoratti M (1992) Modulation of the mitochondrial megachannel by divalent cations and protons. J Biol Chem 267:2940–2946Google Scholar
  107. Tang Y, Zucker RS (1997) Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron 18:483–491CrossRefGoogle Scholar
  108. H. L. Tang, H. M. Tang, M. C. Fung, J. M. Hardwick, (2015) In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci Report 5, 9015 doi: 10.1038/srep09015.
  109. Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB (2000) Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc Natl Acad Sci U S A 97:4666–4671CrossRefGoogle Scholar
  110. Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M (2001) Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem 276:19414–19419CrossRefGoogle Scholar
  111. Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41:1–16. doi: 10.1042/BST20110773 CrossRefGoogle Scholar
  112. Wang W, Fang H, Groom L, Cheng A, Zhang W, Liu J, Wang X, Li K, Han P, Zheng M, Yin J, Mattson MP, Kao JP, Lakatta EG, Sheu SS, Ouyang K, Chen J, Dirksen RT, Cheng H (2008) Superoxide flashes in single mitochondria. Cell 134:279–290. doi: 10.1016/j.cell.2008.06.017) CrossRefGoogle Scholar
  113. Wittig I, Schagger H (2009) Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim Biophys Acta 1787:672–680. doi: 10.1016/j.bbabio.2008.12.016 CrossRefGoogle Scholar
  114. Woodfield K, Ruck A, Brdiczka D, Halestrap AP (1998) published online EpubDec 1 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):287–290CrossRefGoogle Scholar
  115. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59CrossRefGoogle Scholar
  116. Zakharov SD, Li X, Red'ko TP, Dilley RA (1996) published online EpubDec Calcium binding to the subunit c of E. coli ATP-synthase and possible functional implications in energy coupling. J Bioenerg Biomembr 28:483–494CrossRefGoogle Scholar
  117. Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Nelli Mnatsakanyan
    • 1
  • Gisela Beutner
    • 2
  • George A. Porter
    • 2
  • Kambiz N. Alavian
    • 3
  • Elizabeth A. Jonas
    • 1
  1. 1.Department Internal Medicine, Section of EndocrinologyYale UniversityNew HavenUSA
  2. 2.Department of Pediatrics (Cardiology)University of Rochester Medical CenterRochesterUSA
  3. 3.Division of Brain Sciences, Department of MedicineImperial College LondonLondonUK

Personalised recommendations