Skip to main content
SpringerLink
Log in

The Mitochondrial Permeability Transition Pore: Molecular Structure and Function in Health and Disease

  • Chapter
  • First Online:
Molecular Basis for Mitochondrial Signaling

Part of the book series: Biological and Medical Physics, Biomedical Engineering ((BIOMEDICAL))

Abstract

Ion transport across the mitochondrial inner and outer membranes is central to mitochondrial function, including regulation of oxidative phosphorylation and cell death. Although required for ATP production by mitochondria, recent findings have confirmed that 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 and cell death. This chapter will discuss recent advances in understanding the molecular components of mPTP, its regulatory mechanisms during cell death, and its function in diseases of the brain. In contrast to mitochondrial inner membrane uncoupling, enhanced coupling occurs in states of improved mitochondrial efficiency; relative closure of mPTP therefore contributes to cell functions as diverse as cardiac development and synaptic efficacy.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  ADS  Google Scholar 

  • Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Li H, Signore AP, Smith PJ, Gribkoff VK, Jonas EA (2015) The mitochondrial complex v-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole. Mol Pharmacol 87:1–8

    Article  Google Scholar 

  • Alobuia WM, Xia W, Vohra BP (2013) Axon degeneration is key component of neuronal death in amyloid-beta toxicity. Neurochem Int 63:782–789

    Article  Google Scholar 

  • Andrews ZB, Diano S, Horvath TL (2005) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6:829–840

    Article  Google Scholar 

  • Atamna H, Frey WH 2nd (2004) A role for heme in Alzheimer’s disease: heme binds amyloid beta and has altered metabolism. Proc Natl Acad Sci U S A 101:11153–11158

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Baines CP (2009) The mitochondrial permeability transition pore and ischemia-reperfusion injury. Basic Res Cardiol 104:181–188

    Article  Google Scholar 

  • Baines CP (2011) The mitochondrial permeability transition pore and the cardiac necrotic program. Pediatr Cardiol 32:258–262

    Article  Google Scholar 

  • 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.[see comment]. Nature 434:658–662

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Banerjee R, Starkov AA, Beal MF, Thomas B (2009) Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 1792:651–663

    Article  Google Scholar 

  • Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, Rizzuto R, Carafoli E, Nicotera P (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120:275–285

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Beal MF (2007) Mitochondria and neurodegeneration. Novartis Found Symp 287:183–192. discussion 192–186

    Article  Google Scholar 

  • Bernardi P (1999) Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79:1127–1155

    Google Scholar 

  • Bernardi P (2013) The mitochondrial permeability transition pore: a mystery solved? Front Physiol 4:95

    Article  Google Scholar 

  • Bernardi P, Di Lisa F (2015) The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol 78:100–106

    Article  Google Scholar 

  • 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 396:189–195

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  ADS  Google Scholar 

  • Billups B, Forsythe ID (2002) Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J Neurosci 22:5840–5847

    Google Scholar 

  • Blanchard BJ, Thomas VL, Ingram VM (2002) Mechanism of membrane depolarization caused by the Alzheimer Abeta1-42 peptide. Biochem Biophys Res Commun 293:1197–1203

    Article  Google Scholar 

  • Bonora M, Pinton P (2014) Shedding light on molecular mechanisms and identity of mPTP. Mitochondrion 21:11

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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 34:1475. 0

    Article  Google Scholar 

  • Borjesson SI, Elinder F (2008) Structure, function, and modification of the voltage sensor in voltage-gated ion channels. Cell Biochem Biophys 52:149–174

    Article  Google Scholar 

  • Brand MD (2005) The efficiency and plasticity of mitochondrial energy transduction. Biochem Soc Trans 33:897–904

    Article  Google Scholar 

  • Bravo C, Minauro-Sanmiguel F, Morales-Rios E, Rodriguez-Zavala JS, Garcia JJ (2004) Overexpression of the inhibitor protein IF(1) in AS-30D hepatoma produces a higher association with mitochondrial F(1)F(0) ATP synthase compared to normal rat liver: functional and cross-linking studies. J Bioenerg Biomembr 36:257–264

    Article  Google Scholar 

  • Brenner C, Cadiou H, Vieira HL, Zamzami N, Marzo I, Xie Z, Leber B, Andrews D, Duclohier H, Reed JC, Kroemer G (2000) Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene 19:329–336

    Article  Google Scholar 

  • Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke J Cereb Circ 40:e331–e339

    Article  Google Scholar 

  • Budd SL, Nicholls DG (1996) Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells. J Neurochem 67:2282–2291

    Article  Google Scholar 

  • Cabezon E, Runswick MJ, Leslie AG, Walker JE (2001) The structure of bovine IF(1), the regulatory subunit of mitochondrial F-ATPase. EMBO J 20:6990–6996

    Article  Google Scholar 

  • Cadonic C, Sabbir MG, Albensi BC (2015) Mechanisms of mitochondrial dysfunction in Alzheimer’s disease. Mol Neurobiol 53:6078

    Article  Google Scholar 

  • Campanella M, Casswell E, Chong S, Farah Z, Wieckowski MR, Abramov AY, Tinker A, Duchen MR (2008) Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1. Cell Metab 8:13–25

    Article  Google Scholar 

  • Cao G, Minami M, Pei W, Yan C, Chen D, O’Horo C, Graham SH, Chen J (2001) Intracellular Bax translocation after transient cerebral ischemia: implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cereb Blood Flow Metab Off J Intern Soc Cereb Blood Flow Metab 21:321–333

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Cassarino DS, Parks JK, Parker WD Jr, Bennett JP Jr (1999) The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453:49–62

    Article  Google Scholar 

  • Caviston TL, Ketchum CJ, Sorgen PL, Nakamoto RK, Cain BD (1998) Identification of an uncoupling mutation affecting the b subunit of F1F0 ATP synthase in Escherichia coli. FEBS Lett 429:201–206

    Article  Google Scholar 

  • Cha MY, Han SH, Son SM, Hong HS, Choi YJ, Byun J, Mook-Jung I (2012) Mitochondria-specific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death. PLoS One 7:e34929

    Article  ADS  Google Scholar 

  • Cha MY, Cho HJ, Kim C, Jung YO, Kang MJ, Murray ME, Hong HS, Choi YJ, Choi H, Kim DK, Choi H, Kim J, Dickson DW, Song HK, Cho JW, Yi EC, Kim J, Jin SM, Mook-Jung I (2015) Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer’s disease. Hum Mol Genet 24:6492–6504

    Article  Google Scholar 

  • 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 279:31761–31768

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Chen Q, Xu H, Xu A, Ross T, Bowler E, Hu Y, Lesnefsky EJ (2015) Inhibition of Bcl-2 sensitizes mitochondrial permeability transition pore (MPTP) opening in ischemia-damaged mitochondria. PLoS One 10:e0118834

    Article  Google Scholar 

  • 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? Front Oncol 4:235

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci Off J Soc Neurosci 7:369–379

    Google Scholar 

  • 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

    Article  Google Scholar 

  • Clem RJ, Cheng EH, Karp CL, Kirsch DG, Ueno K, Takahashi A, Kastan MB, Griffin DE, Earnshaw WC, Veliuona MA, Hardwick JM (1998) Modulation of cell death by Bcl-XL through caspase interaction. Proc Natl Acad Sci U S A 95:554–559

    Article  ADS  Google Scholar 

  • Couoh-Cardel S, Hsueh YC, Wilkens S, Movileanu L (2016) Yeast V-ATPase proteolipid ring acts as a large-conductance transmembrane protein pore. Sci Rep 6:24774

    Article  ADS  Google Scholar 

  • Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249

    Article  Google Scholar 

  • Crompton M, Ellinger H, Costi A (1988) Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 255:357–360

    Google Scholar 

  • 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 258:729–735

    Article  Google Scholar 

  • Csordas G, Thomas AP, Hajnoczky G (2001) Calcium signal transmission between ryanodine receptors and mitochondria in cardiac muscle. Trends Cardiovasc Med 11:269–275

    Article  Google Scholar 

  • D’Alessandro M, Turina P, Melandri BA (2008) Intrinsic uncoupling in the ATP synthase of Escherichia coli. Biochim Biophys Acta 1777:1518–1527

    Article  Google Scholar 

  • Davies KM, Anselmi C, Wittig I, Faraldo-Gomez JD, Kuhlbrandt W (2012) Structure of the yeast F1Fo-ATP synthase dimer and its role in shaping the mitochondrial cristae. Proc Natl Acad Sci U S A 109:13602–13607

    Article  ADS  Google Scholar 

  • De Stefani D, Rizzuto R (2014) Molecular control of mitochondrial calcium uptake. Biochem Biophys Res Commun 449:373–376

    Article  Google Scholar 

  • Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787:1309–1316

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • DiMauro S, Bonilla E, Lee CP, Schotland DL, Scarpa A, Conn H Jr, Chance B (1976) Luft’s disease. Further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27:217–232

    Article  Google Scholar 

  • Divakaruni AS, Brand MD (2011) The regulation and physiology of mitochondrial proton leak. Physiology 26:192–205

    Article  Google Scholar 

  • Dodson MW, Guo M (2007) Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson’s disease. Curr Opin Neurobiol 17:331–337

    Article  Google Scholar 

  • Drenckhahn JD (2011) Heart development: mitochondria in command of cardiomyocyte differentiation. Dev Cell 21:392–393

    Article  Google Scholar 

  • Du H, Yan SS (2010) Mitochondrial permeability transition pore in Alzheimer’s disease: cyclophilin D and amyloid beta. Biochim Biophys Acta 1802:198–204

    Article  Google Scholar 

  • Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42

    Article  Google Scholar 

  • Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105

    Article  Google Scholar 

  • Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci U S A 107:18670–18675

    Article  ADS  Google Scholar 

  • Du H, Guo L, Wu X, Sosunov AA, McKhann GM, Chen JX, Yan SS (2014) Cyclophilin D deficiency rescues Abeta-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta 1842:2517–2527

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  ADS  Google Scholar 

  • Erturk A, Wang Y, Sheng M (2014) Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms. J Neurosci 34:1672–1688

    Article  Google Scholar 

  • Faccenda D, Tan CH, Duchen MR, Campanella M (2013a) Mitochondrial IF(1) preserves cristae structure to limit apoptotic cell death signaling. Cell Cycle 12:2530–2532

    Article  Google Scholar 

  • Faccenda D, Tan CH, Seraphim A, Duchen MR, Campanella M (2013b) IF1 limits the apoptotic-signalling cascade by preventing mitochondrial remodelling. Cell Death Differ 20:686–697

    Article  Google Scholar 

  • Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400–413

    Article  Google Scholar 

  • Finbow ME, Harrison MA (1997) The vacuolar H+-ATPase: a universal proton pump of eukaryotes. Biochem J 324(Pt 3):697–712

    Article  Google Scholar 

  • Folmes CD, Dzeja PP, Nelson TJ, Terzic A (2012) Mitochondria in control of cell fate. Circ Res 110:526–529

    Article  Google Scholar 

  • Frei B, Richter C (1986) N-methyl-4-phenylpyridine (MMP+) together with 6-hydroxydopamine or dopamine stimulates Ca2+ release from mitochondria. FEBS Lett 198:99–102

    Article  Google Scholar 

  • 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 14:4007–4024

    Google Scholar 

  • Fujita N, Nagahashi A, Nagashima K, Rokudai S, Tsuruo T (1998) Acceleration of apoptotic cell death after the cleavage of Bcl-XL protein by caspase-3-like proteases. Oncogene 17:1295–1304

    Article  Google Scholar 

  • 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

    Article  ADS  Google Scholar 

  • Galluzzi L, Blomgren K, Kroemer G (2009) Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 10:481–494

    Article  Google Scholar 

  • Galonek HL, Hardwick JM (2006) Upgrading the BCL-2 network.[comment]. Nat Cell Biol 8:1317–1319

    Article  Google Scholar 

  • Garcia JJ, Morales-Rios E, Cortes-Hernandez P, Rodriguez-Zavala JS (2006) The inhibitor protein (IF1) promotes dimerization of the mitochondrial F1F0-ATP synthase. Biochemistry 45:12695–12703

    Article  Google Scholar 

  • Gautier CA, Giaime E, Caballero E, Nunez L, Song Z, Chan D, Villalobos C, Shen J (2012) Regulation of mitochondrial permeability transition pore by PINK1. Mol Neurodegener 7:22

    Article  Google Scholar 

  • Gellerich FN, Gizatullina Z, Trumbeckaite S, Nguyen HP, Pallas T, Arandarcikaite O, Vielhaber S, Seppet E, Striggow F (2010) The regulation of OXPHOS by extramitochondrial calcium. Biochim Biophys Acta 1797:1018–1027

    Article  Google Scholar 

  • Gerle C (2016) On the structural possibility of pore-forming mitochondrial FoF1 ATP synthase. Biochim Biophys Acta 1857:1191–1196

    Article  Google Scholar 

  • Giaime E, Yamaguchi H, Gautier CA, Kitada T, Shen J (2012) Loss of DJ-1 does not affect mitochondrial respiration but increases ROS production and mitochondrial permeability transition pore opening. PLoS One 7:e40501

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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 (2013a) Dimers of mitochondrial ATP synthase form the permeability transition pore. PNAS 110:5887–5892

    Article  ADS  Google Scholar 

  • 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 (2013b) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110:5887–5892

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Gottlieb E, Armour SM, Thompson CB (2002) Mitochondrial respiratory control is lost during growth factor deprivation. Proc Natl Acad Sci U S A 99:12801–12806

    Article  ADS  Google Scholar 

  • Guerrieri F, Capozza G, Kalous M, Papa S (1992) Age-related changes of mitochondrial F0F1 ATP synthase. Ann N Y Acad Sci 671:395–402

    Article  ADS  Google Scholar 

  • Gunter TE, Sheu SS (2009) Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim Biophys Acta 1787:1291–1308

    Article  Google Scholar 

  • Guo L, Du H, Yan S, Wu X, McKhann GM, Chen JX, Yan SS (2013) Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer’s neurons. PLoS One 8:e54914

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, Sinclair DA (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging 2:914–923

    Article  Google Scholar 

  • Hajnoczky G, Csordas G, Krishnamurthy R, Szalai G (2000) Mitochondrial calcium signaling driven by the IP3 receptor. J Bioenerg Biomembr 32:15–25

    Article  Google Scholar 

  • 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 268:153–160

    Article  Google Scholar 

  • Harrison M, Durose L, Song CF, Barratt E, Trinick J, Jones R, Findlay JB (2003) Structure and function of the vacuolar H+-ATPase: moving from low-resolution models to high-resolution structures. J Bioenerg Biomembr 35:337–345

    Article  Google Scholar 

  • Hausenloy D, Wynne A, Duchen M, Yellon D (2004) Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 109:1714–1717

    Article  Google Scholar 

  • Haworth RA, Hunter DR (1979) The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch Biochem Biophys 195:460–467

    Article  Google Scholar 

  • Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA (2008) Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmission. J Neurophysiol 99:1515–1522

    Article  Google Scholar 

  • Hirotani M, Zhang Y, Fujita N, Naito M, Tsuruo T (1999) NH2-terminal BH4 domain of Bcl-2 is functional for heterodimerization with Bax and inhibition of apoptosis. J Biol Chem 274:20415–20420

    Article  Google Scholar 

  • Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336

    Article  ADS  Google Scholar 

  • Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15:411–421

    Article  Google Scholar 

  • 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

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Hubbard MJ, McHugh NJ (1996) Mitochondrial ATP synthase F1-beta-subunit is a calcium-binding protein. FEBS Lett 391:323–329

    Article  Google Scholar 

  • Hunter DR, Haworth RA (1979a) The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch Biochem Biophys 195:468–477

    Article  Google Scholar 

  • Hunter DR, Haworth RA (1979b) The Ca2+−induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195:453–459

    Article  Google Scholar 

  • Huser J, Blatter LA (1999) Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore. Biochem J 343(Pt 2):311–317

    Article  Google Scholar 

  • Jennings RB, Reimer KA, Steenbergen C (1991) Effect of inhibition of the mitochondrial ATPase on net myocardial ATP in total ischemia. J Mol Cell Cardiol 23:1383–1395

    Article  Google Scholar 

  • Jonas E (2006) BCL-xL regulates synaptic plasticity. Mol Interv 6:208–222

    Article  Google Scholar 

  • Jonas EA (2009) Molecular participants in mitochondrial cell death channel formation during neuronal ischemia. Exp Neurol 218:203–212

    Article  Google Scholar 

  • Jonas EA, Knox RJ, Kaczmarek LK (1997) Giga-ohm seals on intracellular membranes: a technique for studying intracellular ion channels in intact cells. Neuron 19:7–13

    Article  Google Scholar 

  • Jonas EA, Buchanan J, Kaczmarek LK (1999) Prolonged activation of mitochondrial conductances during synaptic transmission. Science 286:1347–1350

    Article  Google Scholar 

  • 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 23:8423–8431

    Google Scholar 

  • Jonas EA, Hickman JA, Chachar M, Polster BM, Brandt TA, Fannjiang Y, Ivanovska I, Basanez G, Kinnally KW, Zimmerberg J, Hardwick JM, Kaczmarek LK (2004) Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals. Proc Natl Acad Sci USA 101:13590–13595

    Article  ADS  Google Scholar 

  • Jonas EA, Hickman JA, Hardwick JM, Kaczmarek LK (2005) Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse. J Biol Chem 280:4491–4497

    Article  Google Scholar 

  • Jonas EA, Porter GA, Alavian KN (2014) Bcl-xL in neuroprotection and plasticity. Front Physiol 5:355

    Article  Google Scholar 

  • Jonckheere AI, Smeitink JA, Rodenburg RJ (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35:211–225

    Article  Google Scholar 

  • Jones PC, Harrison MA, Kim YI, Finbow ME, Findlay JB (1995) The first putative transmembrane helix of the 16 kDa proteolipid lines a pore in the Vo sector of the vacuolar H(+)-ATPase. Biochem J 312(Pt 3):739–747

    Article  Google Scholar 

  • Kang JS, Tian JH, Pan PY, Zald P, Li C, Deng C, Sheng ZH (2008) Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132:137–148

    Article  Google Scholar 

  • Karch J, Molkentin JD (2014) Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci USA 111:10396–10397

    Article  ADS  Google Scholar 

  • Kinnally KW, Campo ML, Tedeschi H (1989) Mitochondrial channel activity studied by patch-clamping mitoplasts. J Bioenerg Biomembr 21:497–506

    Article  Google Scholar 

  • 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 427:461–465

    Article  ADS  Google Scholar 

  • Konig T, Troder SE, Bakka K, Korwitz A, Richter-Dennerlein R, Lampe PA, Patron M, Muhlmeister M, Guerrero-Castillo S, Brandt U, Decker T, Lauria I, Paggio A, Rizzuto R, Rugarli EI, De Stefani D, Langer T (2016) The m-AAA protease associated with neurodegeneration limits MCU activity in mitochondria. Mol Cell 64:148–162

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H, Matsumoto T (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15:883–895

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777:946–952

    Article  Google Scholar 

  • Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501

    Article  Google Scholar 

  • 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 105:2169–2174

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Lindsten T et al (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399

    Article  Google Scholar 

  • Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490

    Article  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    Article  Google Scholar 

  • Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126

    Article  Google Scholar 

  • Maltecca F, Baseggio E, Consolato F, Mazza D, Podini P, Young SM Jr, Drago I, Bahr BA, Puliti A, Codazzi F, Quattrini A, Casari G (2015) Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J Clin Invest 125:263–274

    Article  Google Scholar 

  • Mandel M, Moriyama Y, Hulmes JD, Pan YC, Nelson H, Nelson N (1988) cDNA sequence encoding the 16-kDa proteolipid of chromaffin granules implies gene duplication in the evolution of H+-ATPases. Proc Natl Acad Sci USA 85:5521–5524

    Article  ADS  Google Scholar 

  • Mannella CA, Kinnally KW (2008) Reflections on VDAC as a voltage-gated channel and a mitochondrial regulator. J Bioenerg Biomembr 40:149–155

    Article  Google Scholar 

  • Martin LJ, Semenkow S, Hanaford A, Wong M (2014) Mitochondrial permeability transition pore regulates Parkinson’s disease development in mutant alpha-synuclein transgenic mice. Neurobiol Aging 35:1132–1152

    Article  Google Scholar 

  • Massaad CA, Klann E (2011) Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal 14:2013–2054

    Article  Google Scholar 

  • Matsumoto S, Friberg H, Ferrand-Drake M, Wieloch T (1999) Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab Off J Intern Soc Cereb Blood Flow Metab 19:736–741

    Article  Google Scholar 

  • Matsushita K, Wu Y, Qiu J, Lang-Lazdunski L, Hirt L, Waeber C, Hyman BT, Yuan J, Moskowitz MA (2000) Fas receptor and neuronal cell death after spinal cord ischemia. J Neurosci Off J Soc Neurosci 20:6879–6887

    Google Scholar 

  • 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

    Article  Google Scholar 

  • McGeoch JE, Guidotti G (1997) A 0.1-700 Hz current through a voltage-clamped pore: candidate protein for initiator of neural oscillations. Brain Res 766:188–194

    Article  Google Scholar 

  • McGeoch JE, McGeoch MW (2008) Entrapment of water by subunit c of ATP synthase. J R Soc Interface R Soc 5:311–318

    Article  Google Scholar 

  • McGuinness O, Yafei N, Costi A, Crompton M (1990) The presence of two classes of high-affinity cyclosporin A binding sites in mitochondria. Evidence that the minor component is involved in the opening of an inner-membrane Ca(2+)-dependent pore. Eur J Biochem FEBS 194:671–679

    Article  Google Scholar 

  • Meier T, Matthey U, Henzen F, Dimroth P, Muller DJ (2001) The central plug in the reconstituted undecameric c cylinder of a bacterial ATP synthase consists of phospholipids. FEBS Lett 505:353–356

    Article  Google Scholar 

  • Meyer FB (1989) Calcium, neuronal hyperexcitability and ischemic injury. Brain Res Brain Res Rev 14:227–243

    Article  ADS  Google Scholar 

  • Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144–148

    Article  ADS  Google Scholar 

  • Miyawaki T, Mashiko T, Ofengeim D, Flannery RJ, Noh KM, Fujisawa S, Bonanni L, Bennett MV, Zukin RS, Jonas EA (2008) Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons. Proc Natl Acad Sci U S A 105:4892–4897

    Article  ADS  Google Scholar 

  • 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

    Article  ADS  Google Scholar 

  • 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 U S A 95:14681–14686

    Article  ADS  Google Scholar 

  • Neher E, Sakaba T (2008) Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59:861–872

    Article  Google Scholar 

  • 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 286:40184–40192

    Article  Google Scholar 

  • Nicholls DG, Rial E (1999) A history of the first uncoupling protein, UCP1. J Bioenerg Biomembr 31:399–406

    Article  Google Scholar 

  • Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989

    Article  ADS  Google Scholar 

  • Nishizawa Y (2001) Glutamate release and neuronal damage in ischemia. Life Sci 69:369–381

    Article  Google Scholar 

  • Norris U, Karp PE, Fimmel AL (1992) Mutational analysis of the glycine-rich region of the c subunit of the Escherichia coli F0F1 ATPase. J Bacteriol 174:4496–4499

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Ofengeim D, Chen YB, Miyawaki T, Li H, Sacchetti S, Flannery RJ, Alavian KN, Pontarelli F, Roelofs BA, Hickman JA, Hardwick JM, Zukin RS, Jonas EA (2012) N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death. Nat Neurosci 15:574–580

    Article  Google Scholar 

  • Olsen KM, Sheng M (2012) NMDA receptors and BAX are essential for Abeta impairment of LTP. Sci Rep 2:225

    Article  ADS  Google Scholar 

  • Pang ZP, Cao P, Xu W, Sudhof TC (2010) Calmodulin controls synaptic strength via presynaptic activation of calmodulin kinase II. J Neurosci 30:4132–4142

    Article  Google Scholar 

  • Park HA, Licznerski P, Alavian KN, Shanabrough M, Jonas EA (2014) Bcl-xL is necessary for neurite outgrowth in hippocampal neurons. Antioxid Redox Signal 22:93

    Article  Google Scholar 

  • Park HA, Licznerski P, Alavian KN, Shanabrough M, Jonas EA (2015) Bcl-xL is necessary for neurite outgrowth in hippocampal neurons. Antioxid Redox Signal 22:93–108

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Pedersen PL (1994) ATP synthase. The machine that makes ATP. Curr Biol CB 4:1138–1141

    Article  Google Scholar 

  • Pedersen PL, Hullihen J (1978) 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 253:2176–2183

    Google Scholar 

  • Peters C, Bayer MJ, Buhler S, Andersen JS, Mann M, Mayer A (2001) Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature 409:581–588

    Article  ADS  Google Scholar 

  • Petronilli V, Szabo I, Zoratti M (1989) The inner mitochondrial membrane contains ion-conducting channels similar to those found in bacteria. FEBS Lett 259:137–143

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Petronilli V, Penzo D, Scorrano L, Bernardi P, Di Lisa F (2001) The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem 276:12030–12034

    Article  Google Scholar 

  • Pullman ME, Monroy GC (1963) A naturally occurring inhibitor of mitochondrial adenosine triphosphatase. J Biol Chem 238:3762–3769

    Google Scholar 

  • Qiao H, Koya RC, Nakagawa K, Tanaka H, Fujita H, Takimoto M, Kuzumaki N (2005) Inhibition of Alzheimer’s amyloid-beta peptide-induced reduction of mitochondrial membrane potential and neurotoxicity by gelsolin. Neurobiol Aging 26:849–855

    Article  Google Scholar 

  • Raffaello A, De Stefani D, Rizzuto R (2012) The mitochondrial Ca(2+) uniporter. Cell Calcium 52:16–21

    Article  Google Scholar 

  • Rao VK, Carlson EA, Yan SS (2014) Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta 1842:1267–1272

    Article  Google Scholar 

  • Rasheed MZ, Tabassum H, Parvez S (2016) Mitochondrial permeability transition pore: a promising target for the treatment of Parkinson’s disease. Protoplasma 254:33

    Article  Google Scholar 

  • Rasola A, Bernardi P (2011) Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium 50:222–233

    Article  Google Scholar 

  • Reddy PH (2009) Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp Neurol 218:286–292

    Article  Google Scholar 

  • Reed DJ, Savage MK (1995) Influence of metabolic inhibitors on mitochondrial permeability transition and glutathione status. Biochim Biophys Acta 1271:43–50

    Article  Google Scholar 

  • Reynolds IJ (1999) Mitochondrial membrane potential and the permeability transition in excitotoxicity. Ann NY Acad Sci 893:33–41

    Article  ADS  Google Scholar 

  • Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408

    Article  Google Scholar 

  • Rizzuto R, Bernardi P, Pozzan T (2000) Mitochondria as all-round players of the calcium game. J Physiol 529(Pt 1):37–47

    Article  Google Scholar 

  • 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) Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 1787:1342–1351

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Rostovtseva TK, Bezrukov SM (2012) VDAC inhibition by tubulin and its physiological implications. Biochim Biophys Acta 1818:1526–1535

    Article  Google Scholar 

  • Rostovtseva T, Colombini M (1997) VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function. Biophys J 72:1954–1962

    Article  Google Scholar 

  • Rouslin W (1991) Regulation of the mitochondrial ATPase in situ in cardiac muscle: role of the inhibitor subunit. J Bioenerg Biomembr 23:873–888

    Article  Google Scholar 

  • Sanchez-Cenizo L, Formentini L, Aldea M, Ortega AD, Garcia-Huerta P, Sanchez-Arago M, Cuezva JM (2010) Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+−ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem 285:25308–25313

    Article  Google Scholar 

  • 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 U S A 102:12005–12010

    Article  ADS  Google Scholar 

  • Schneggenburger R, Neher E (2005) Presynaptic calcium and control of vesicle fusion. Curr Opin Neurobiol 15:266–274

    Article  Google Scholar 

  • Schon EA, Manfredi G (2003) Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 111:303–312

    Article  Google Scholar 

  • Schwab BL, Guerini D, Didszun C, Bano D, Ferrando-May E, Fava E, Tam J, Xu D, Xanthoudakis S, Nicholson DW, Carafoli E, Nicotera P (2002) Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death Differ 9:818–831

    Article  Google Scholar 

  • Seidlmayer LK, Blatter LA, Pavlov E, Dedkova EN (2012) Inorganic polyphosphate – an unusual suspect of the mitochondrial permeability transition mystery. Channels 6:463–467

    Article  Google Scholar 

  • Seng NS, Megyesi J, Tarcsafalvi A, Price PM (2016) Mimicking Cdk2 phosphorylation of Bcl-xL at Ser73 results in caspase activation and Bcl-xL cleavage. Cell Death Discov 2:16001–16006

    Article  Google Scholar 

  • Shanmughapriya S et al (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol Cell 60:47–62

    Article  Google Scholar 

  • Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487

    Article  ADS  Google Scholar 

  • 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 123:4117–4127

    Article  Google Scholar 

  • 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 123:894–902

    Article  Google Scholar 

  • Sorgato MC, Keller BU, Stuhmer W (1987) Patch-clamping of the inner mitochondrial membrane reveals a voltage-dependent ion channel. Nature 330:498–500

    Article  ADS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Sugioka R, Shimizu S, Funatsu T, Tamagawa H, Sawa Y, Kawakami T, Tsujimoto Y (2003) BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo. Oncogene 22:8432–8440

    Article  Google Scholar 

  • Supnet C, Bezprozvanny I (2010) The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 47:183–189

    Article  Google Scholar 

  • Szabo I, Zoratti M (1991) The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 266:3376–3379

    Google Scholar 

  • Szabo I, Bernardi P, Zoratti M (1992) Modulation of the mitochondrial megachannel by divalent cations and protons. J Biol Chem 267:2940–2946

    Google Scholar 

  • Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47:122–129

    Article  Google Scholar 

  • Tang Y, Zucker RS (1997) Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron 18:483–491

    Article  Google Scholar 

  • Thomas B, Banerjee R, Starkova NN, Zhang SF, Calingasan NY, Yang L, Wille E, Lorenzo BJ, Ho DJ, Beal MF, Starkov A (2012) Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson’s disease. Antioxid Redox Signal 16:855–868

    Article  Google Scholar 

  • 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 276:19414–19419

    Article  Google Scholar 

  • Veas-Perez de Tudela M, Delgado-Esteban M, Maestre C, Bobo-Jimenez V, Jimenez-Blasco D, Vecino R, Bolanos JP, Almeida A (2015) Regulation of Bcl-xL-ATP synthase interaction by mitochondrial cyclin B1-cyclin-dependent kinase-1 determines neuronal survival. J Neurosci 35:9287–9301

    Article  Google Scholar 

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102:43–53

    Article  Google Scholar 

  • Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41:1–16

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Watt IN, Montgomery MG, Runswick MJ, Leslie AG, Walker JE (2010) Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci U S A 107:16823–16827

    Article  ADS  Google Scholar 

  • Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R (2010) Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 13:190–196

    Article  Google Scholar 

  • Wittig I, Schagger H (2009) Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim Biophys Acta 1787:672–680

    Article  Google Scholar 

  • 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):287–290

    Article  Google Scholar 

  • Yamada EW, Huzel NJ (1992) Distribution of the ATPase inhibitor proteins of mitochondria in mammalian tissues including fibroblasts from a patient with Luft’s disease. Biochim Biophys Acta 1139:143–147

    Article  Google Scholar 

  • Zakharov SD, Li X, Red’ko TP, Dilley RA (1996) Calcium binding to the subunit c of E. coli ATP-synthase and possible functional implications in energy coupling. J Bioenerg Biomembr 28:483–494

    Article  Google Scholar 

  • 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 19:6342–6350

    Article  Google Scholar 

  • Zanellati MC, Monti V, Barzaghi C, Reale C, Nardocci N, Albanese A, Valente EM, Ghezzi D, Garavaglia B (2015) Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts. Front Genet 6:78

    Article  Google Scholar 

  • Zhu J, Rebecchi MJ, Glass PS, Brink PR, Liu L (2013) Interactions of GSK-3beta with mitochondrial permeability transition pore modulators during preconditioning: age-associated differences. J Gerontol A Biol Sci Med Sci 68:395–403

    Article  Google Scholar 

  • Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Leonard Kaczmarek for the artwork in Fig. 3.1.

Author information

Author notes

    Authors and Affiliations

    1. Department Internal Medicine, Section of Endocrinology, Yale University School of Medicine, 208020, New Haven, CT, 06520, USA

      Elizabeth A. Jonas, Nelli Mnatsakanyan, Han-A. Park, Nikita Mehta & Rongmin Chen

    2. Department of Pediatrics (Cardiology), University of Rochester Medical Center, Rochester, NY, USA

      George A. Porter Jr. & Gisela Beutner

    3. Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK

      Kambiz N. Alavian

    Authors
    1. Elizabeth A. Jonas
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. George A. Porter Jr.
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Gisela Beutner
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Nelli Mnatsakanyan
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Han-A. Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Nikita Mehta
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Rongmin Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Kambiz N. Alavian
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Elizabeth A. Jonas .

    Editor information

    Editors and Affiliations

    1. Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

      Tatiana K. Rostovtseva

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2017 Springer International Publishing AG

    About this chapter

    Cite this chapter

    Jonas, E.A. et al. (2017). The Mitochondrial Permeability Transition Pore: Molecular Structure and Function in Health and Disease. 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_3

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation