Abstract
Mitochondrial permeability transition is a phenomenon of sudden increase in the permeability on the inner membrane in response to excessive calcium accumulation inside the mitochondrial matrix. Permeability transition is caused by the opening of the large nonselective channel – mitochondrial permeability transition pore (mPTP). mPTP opening leads to the depolarization of the mitochondrial membrane and, as a result, to the disruption of the ATP synthesis. Prevention of mPTP is protective against stress induced cell death, which makes it a potentially important pharmacological target. Here we review current opinions regarding the molecular structure of mPTP and mechanisms of its activation by calcium. We discuss the importance of calcium-phosphate interactions in the process of mPTP activation. Further we review recently proposed models of mPTP formation that involve participation of the oligomers of the C subunit of the mitochondrial ATP synthase and discuss potential roles of inorganic polyphosphate and calcium in transition of the C subunit oligomers into mPTP channel. Finally, we review potential physiological roles of mPTP.
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References
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(29):10580–10585
Altschuld RA, Hohl CM, Castillo LC, Garleb AA, Starling RC, Brierley GP (1992) Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am J Phys 262(6 Pt 2):H1699–H1704
Bernardi P, Bonaldo P (2008) Dysfunction of mitochondria and sarcoplasmic reticulum in the pathogenesis of collagen VI muscular dystrophies. Ann N Y Acad Sci 1147:303–311
Bernardi P, Forte M (2015) Commentary: SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Front Physiol 6:320
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(4):1111–1155
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(4):674–683
Brdiczka D (1991) Contact sites between mitochondrial envelope membranes. Structure and function in energy- and protein-transfer. Biochim Biophys Acta 1071(3):291–312
Brenner C, Moulin M (2012) Physiological roles of the permeability transition pore. Circ Res 111(9):1237–1247
Broekemeier KM, Dempsey ME, Pfeiffer DR (1989) Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem 264(14):7826–7830
Brustovetsky N, Tropschug M, Heimpel S, Heidkamper D, Klingenberg M (2002) A large Ca2+-dependent channel formed by recombinant ADP/ATP carrier from Neurospora crassa resembles the mitochondrial permeability transition pore. Biochemistry 41(39):11804–11811
Carew JS, Huang P (2002) Mitochondrial defects in cancer. Mol Cancer 1:9
Castuma CE, Huang R, Kornberg A, Reusch RN (1995) Inorganic polyphosphates in the acquisition of competence in Escherichia coli. J Biol Chem 270(22):12980–12983
Chalmers S, Nicholls DG (2003) The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J Biol Chem 278(21):19062–19070
Chen H, Chan DC (2009) Mitochondrial dynamics – fusion, fission, movement, and mitophagy – in neurodegenerative diseases. Hum Mol Genet 18(R2):R169–R176
Christofferson DE, Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22(2):263–268
Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354
Curtis JM, Hahn WS, Long EK, Burrill JS, Arriaga EA, Bernlohr DA (2012) Protein carbonylation and metabolic control systems. Trends Endocrinol Metab 23(8):399–406
Elustondo PA, Negoda A, Kane CL, Kane DA, Pavlov EV (2015) Spermine selectively inhibits high-conductance, but not low-conductance calcium-induced permeability transition pore. Biochim Biophys Acta 1847(2):231–240
Elustondo PA, Nichols M, Negoda A, Thirumaran A, Zakharian E, Robertson GS, Pavlov EV (2016) Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate. Cell Death Discov 2:16070
Fiskum G (2000) Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma 17(10):843–855
Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19(1):107–120
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(15):5887–5892
Giralt A, Villarroya F (2012) SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. Biochem J 444(1):1–10
Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305(5684):626–629
Greenawalt JW, Rossi CS, Lehninger AL (1964) Effect of active accumulation of calcium and phosphate ions on the structure of rat liver mitochondria. J Cell Biol 23:21–38
Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46(6):821–831
Halestrap AP, Connern CP, Griffiths EJ, Kerr PM (1997) Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol Cell Biochem 174(1–2):167–172
Haworth RA, Hunter DR (1979) The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch Biochem Biophys 195(2):460–467
He L, Lemasters JJ (2002) Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett 512(1–3):1–7
Hunter DR, Haworth RA (1979a) The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195(2):453–459
Hunter DR, Haworth RA (1979b) The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch Biochem Biophys 195(2):468–477
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(1–2):33–50
Ichas F, Jouaville LS, Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89(7):1145–1153
Kennedy EP, Lehninger AL (1949) Oxidation of fatty acids and tricarboxylic acid cycle intermediates by isolated rat liver mitochondria. J Biol Chem 179(2):957–972
Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304(3):463–470
Kinnally KW, Zorov D, Antonenko Y, Perini S (1991) Calcium modulation of mitochondrial inner membrane channel activity. Biochem Biophys Res Commun 176(3):1183–1188
Kinnally KW, Lohret TA, Campo ML, Mannella CA (1996) Perspectives on the mitochondrial multiple conductance channel. J Bioenerg Biomembr 28(2):115–123
Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427(6972):360–364
Kristian T, Pivovarova NB, Fiskum G, Andrews SB (2007) Calcium-induced precipitate formation in brain mitochondria: composition, calcium capacity, and retention. J Neurochem 102(4):1346–1356
Kwong JQ, Molkentin JD (2015) Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab 21(2):206–214
Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185(8):1481–1486
Marcil M, Bourduas K, Ascah A, Burelle Y (2006) Exercise training induces respiratory substrate-specific decrease in Ca2+-induced permeability transition pore opening in heart mitochondria. Am J Physiol Heart Circ Physiol 290(4):H1549–H1557
Martel C, Huynh le H, Garnier A, Ventura-Clapier R, Brenner C (2012) Inhibition of the mitochondrial permeability transition for cytoprotection: direct versus indirect mechanisms. Biochem Res Int 2012:213403
Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC, Kroemer G (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 187(8):1261–1271
Mnatsakanyan N, Beutner G, Porter GA, Alavian KN, Jonas EA (2016) Physiological roles of the mitochondrial permeability transition pore. J Bioenerg Biomembr 49:13–25.
Muro C, Grigoriev SM, Pietkiewicz D, Kinnally KW, Campo ML (2003) Comparison of the TIM and TOM channel activities of the mitochondrial protein import complexes. Biophys J 84(5):2981–2989
Nicholls DG, Chalmers S (2004) The integration of mitochondrial calcium transport and storage. J Bioenerg Biomembr 36(4):277–281
Nicotera P, Orrenius S (1998) The role of calcium in apoptosis. Cell Calcium 23(2–3):173–180
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(4):2614–2625
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(2):725–734
Rodriguez-Enriquez S, He L, Lemasters JJ (2004) Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol 36(12):2463–2472
Schonfeld P, Wieckowski MR, Wojtczak L (2000) Long-chain fatty acid-promoted swelling of mitochondria: further evidence for the protonophoric effect of fatty acids in the inner mitochondrial membrane. FEBS Lett 471(1):108–112
Seebach D, Fritz MG (1999) Detection, synthesis, structure, and function of oligo(3-hydroxyalkanoates): contributions by synthetic organic chemists. Int J Biol Macromol 25(1–3):217–236
Shanmughapriya S, Rajan S, Hoffman NE, Higgins AM, Tomar D, Nemani N, Hines KJ, Smith DJ, Eguchi A, Vallem S, Shaikh F, Cheung M, Leonard NJ, Stolakis RS, Wolfers MP, Ibetti J, Chuprun JK, Jog NR, Houser SR, Koch WJ, Elrod JW, Madesh M (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol Cell 60(1):47–62
Smithen M, Elustondo PA, Winkfein R, Zakharian E, Abramov AY, Pavlov E (2013) Role of polyhydroxybutyrate in mitochondrial calcium uptake. Cell Calcium 54(2):86–94
Solesio ME, Demirkhanyan L, Zakharian E, Pavlov EV (2016a) Contribution of inorganic polyphosphate towards regulation of mitochondrial free calcium. Biochim Biophys Acta 1860(6):1317–1325
Solesio ME, Elustondo PA, Zakharian E, Pavlov EV (2016b) Inorganic polyphosphate (polyP) as an activator and structural component of the mitochondrial permeability transition pore. Biochem Soc Trans 44(1):7–12
Szabo I, Zoratti M (1992) The mitochondrial megachannel is the permeability transition pore. J Bioenerg Biomembr 24(1):111–117
Szabo I, Bernardi P, Zoratti M (1992) Modulation of the mitochondrial megachannel by divalent cations and protons. J Biol Chem 267(5):2940–2946
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(2):206–210
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714
Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM (2012) p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149(7):1536–1548
Vyssokikh MY, Brdiczka D (2003) The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis. Acta Biochim Pol 50(2):389–404
Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41(1):1–16
Zamzami N, Marzo I, Susin SA, Brenner C, Larochette N, Marchetti P, Reed J, Kofler R, Kroemer G (1998) The thiol crosslinking agent diamide overcomes the apoptosis-inhibitory effect of Bcl-2 by enforcing mitochondrial permeability transition. Oncogene 16(8):1055–1063
Zamzami N, El Hamel C, Maisse C, Brenner C, Munoz-Pinedo C, Belzacq AS, Costantini P, Vieira H, Loeffler M, Molle G, Kroemer G (2000) Bid acts on the permeability transition pore complex to induce apoptosis. Oncogene 19(54):6342–6350
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Authors would like to acknowledge the support from the American Heart Association and from the National Institute of Health.
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Solesio, M.E., Pavlov, E.V. (2017). Mitochondrial Calcium Uptake in Activation of the Permeability Transition Pore and Cell Death. In: Rostovtseva, T. (eds) Molecular Basis for Mitochondrial Signaling. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-55539-3_4
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