Skip to main content
SpringerLink
Log in

Mitochondrial Ca2+ and regulation of the permeability transition pore

  • Mini-review
  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

The mitochondrial permeability transition pore was originally described in the 1970’s as a Ca2+ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+ in modulating the pore’s open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/ nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

2-Oxoglutarate dehydrogenase:

(2-ODH)

Aconitase:

(ACON)

Adenine nucleotide translocator:

(ANT)

Alpha ketoglutarate dehydrogenase:

(α-KDH)

Calcium retention capacity:

(CRC)

Circularly permuted yellow fluorescence protein:

(cpYFP)

Citrate synthase:

(CS)

Complex I-V:

(CxI-V)

Cyclophilin D:

(CypD)

Cyclosporine A:

(CsA)

Dynamin-like protein 1:

(DLP1)

Electron transport chain:

(ETC)

Essential MCU regulator:

(EMRE)

Fumarase:

(Fum)

Glioblastoma amplified sequence:

(GBAS)

Glycogen synthase kinase 3 beta:

(GSK-3β)

Hexokinase:

(HK)

Inner mitochondrial membrane:

(IMM)

Inorganic phosphate:

(Pi)

Ischemia reperfusion:

(I/R)

Isocitrate dehydrogenase:

(IDH)

Leucine Zipper-EF-Hand Containing Transmembrane Protein:

(Letm1)

Na+/Ca2+ Li+-permeable exchanger:

(NCLX)

Malate dehydrogenase:

(MDH)

Mitofusin 2:

(MFN2)

Mitochondrial benzodiazepine receptor:

(TSPO)

Mitochondrial calcium uniporter:

(MCU)

Mitochondrial calcium uniporter regulator 1:

(MCUR)1

Mitochondrial calcium uptake:

(MICU)

Mitochondrial creatine kinase:

(mtCK)

Mitochondrial permeability transition pore:

(mPTP)

Mitochondria membrane potential:

(ΔΨm)

Mitochondrial ryanodine receptor Type 1:

(mRYR1)

N-ethylmaleimide:

(NEM)

Nitric oxide synthase:

(NOS)

Oligomycin sensitivity conferring protein:

(OSCP)

Outer mitochondria membrane:

(OMM)

Phenylarsine oxide:

(PhAsO)

Phosphate carrier:

(PiC)

Polyphosphate:

(PolyP)

Pyruvate dehydrogenase:

(PDH)

Rapid mode of uptake:

(RaM)

Reactive nitrogen species:

(RNS)

Reactive oxygen species:

(ROS)

S-nitrosylation:

(SNO)

S-nitrosoglutathione:

(GSNO)

Sarco/endoplasmic reticulum Ca2+-ATPase:

(SERCA)

Sirtuin 3:

(SIRT3)

Spastic paraplegia 7:

(SPG7)

Superoxide dismutase 2:

(SOD2)

Tricarboxylic acid:

(TCA)

Voltage dependent anion channel:

(VDAC)

References

  • Abramov AY, Fraley C, Diao CT, et al. (2007) Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. Proc Natl Acad Sci 104:18091–18096. doi:10.1073/pnas.0708959104

    Article  CAS  Google Scholar 

  • Alavian KN, Beutner G, Lazrove E, et al. (2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci 111:10580–10585. doi:10.1073/pnas.1401591111

    Article  CAS  Google Scholar 

  • Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    Article  CAS  Google Scholar 

  • Altschuld RA, Hohl CM, Castillo LC, et al. (1992) Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am J Phys 262:H1699–H1704

    CAS  Google Scholar 

  • Arakaki N, Ueyama Y, Hirose M, et al. (2001) Stoichiometry of subunit e in rat liver mitochondrial H(+)-ATP synthase and membrane topology of its putative Ca(2+)-dependent regulatory region. Biochim Biophys Acta 1504:220–228

    Article  CAS  Google Scholar 

  • Arrington DD, Van Vleet TR, Schnellmann RG (2006) Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. Am J Physiol, Cell Physiol 291:C1159–C1171. doi:10.1152/ajpcell.00207.2006

    Article  CAS  Google Scholar 

  • Baines CP, Kaiser RA, Purcell NH, et al. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662. doi:10.1038/nature03434

    Article  CAS  Google Scholar 

  • Baines CP, Kaiser RA, Sheiko T, et al. (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555. doi:10.1038/ncb1575

    Article  CAS  Google Scholar 

  • Bao H, Ge Y, Zhuang S, et al. (2012) Inhibition of glycogen synthase kinase-3β prevents NSAID-induced acute kidney injury. Kidney Int 81:662–673. doi:10.1038/ki.2011.443

    Article  CAS  Google Scholar 

  • Barsukova A, Komarov A, Hajnóczky G, et al. (2011) Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. Eur J Neurosci 33:831–842. doi:10.1111/j.1460-9568.2010.07576.x

    Article  Google Scholar 

  • Basso E, Fante L, Fowlkes J, et al. (2005) Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J Biol Chem 280:18558–18561. doi:10.1074/jbc.C500089200

    Article  CAS  Google Scholar 

  • Basso E, Petronilli V, Forte MA, Bernardi P (2008) Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin a and by cyclophilin D ablation. J Biol Chem 283:26307–26311. doi:10.1074/jbc.C800132200

    Article  CAS  Google Scholar 

  • Baughman JM, Perocchi F, Girgis HS, et al. (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345. doi:10.1038/nature10234

    Article  CAS  Google Scholar 

  • Bergeaud M, Mathieu L, Guillaume A, et al. (2013) Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F1F0-ATP synthase. Cell Cycle 12:2781–2793. doi:10.4161/cc.25870

    Article  CAS  Google Scholar 

  • Bernardi P, Vassanelli S, Veronese P, et al. (1992) Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations J Biol Chem 267:2934–2939

    CAS  Google Scholar 

  • Bernardi P, Veronese P, Petronilli V (1993) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore. I. Evidence for two separate Me2+ binding sites with opposing effects on the pore open probability. J Biol Chem 268:1005–1010

    CAS  Google Scholar 

  • Bernardi P, Rasola A, Forte M, Lippe G (2015) The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol Rev 95:1111–1155. doi:10.1152/physrev.00001.2015

    Article  Google Scholar 

  • Beutner G (2001) Identification of a ryanodine receptor in rat heart mitochondria. J Biol Chem 276:21482–21488. doi:10.1074/jbc.M101486200

    Article  CAS  Google Scholar 

  • Beutner G, Ruck A, Riede B, et al. (1996) Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore. FEBS Lett 396:189–195

    Article  CAS  Google Scholar 

  • Bochaton T, Crola-Da-Silva C, Pillot B, et al. (2015) Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D. J Mol Cell Cardiol 84:61–69. doi:10.1016/j.yjmcc.2015.03.017

    Article  CAS  Google Scholar 

  • Bonora M, Pinton P (2014) The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Front Oncol 4:302. doi:10.3389/fonc.2014.00302

    Article  Google Scholar 

  • Bonora M, Bononi A, De Marchi E, et al. (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

    Article  CAS  Google Scholar 

  • Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160:1115–1127. doi:10.1083/jcb.200212059

    Article  CAS  Google Scholar 

  • Brookes PS (2004a) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. AJP: Cell Physiology 287:C817–C833. doi:10.1152/ajpcell.00139.2004

    CAS  Google Scholar 

  • Brookes PS (2004b) Mitochondrial nitric oxide synthase. MITOCH 3:187–204. doi:10.1016/j.mito.2003.10.001

    Article  CAS  Google Scholar 

  • Brookes P, Darley-Usmar VM (2002) Hypothesis: the mitochondrial NO(*) signaling pathway, and the transduction of nitrosative to oxidative cell signals: an alternative function for cytochrome C oxidase. Free Radic Biol Med 32:370–374

    Article  CAS  Google Scholar 

  • Carraro M, Giorgio V, Ileikyte J, et al (2014) Channel Formation by Yeast F-ATP Synthase and the Role of Dimerization in the Mitochondrial Permeability Transition. Journal of Biological Chemistry 289:jbc.C114.559633–15985. doi: 10.1074/jbc.C114.559633

  • Chalmers S, Nicholls DG (2003) The relationship between free and Total calcium concentrations in the matrix of liver and brain mitochondria. J Biol Chem 278:19062–19070. doi:10.1074/jbc.M212661200

    Article  CAS  Google Scholar 

  • Chen Q, Lesnefsky EJ (2015) Heart mitochondria and calpain 1: location, function, and targets. BBA - Molecular Basis of Disease:1–34. doi:10.1016/j.bbadis.2015.08.004

  • Chen M, Won D-J, Krajewski S, Gottlieb RA (2002) Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem 277:29181–29186. doi:10.1074/jbc.M204951200

    Article  CAS  Google Scholar 

  • Chen Q, Paillard M, Gomez L, et al. (2011) Activation of mitochondrial μ-calpain increases AIF cleavage in cardiac mitochondria during ischemia–reperfusion. Biochem Biophys Res Commun 415:533–538. doi:10.1016/j.bbrc.2011.10.037

    Article  CAS  Google Scholar 

  • Chen B, Xu M, Zhang H, et al. (2013) Cisplatin-induced non-apoptotic death of pancreatic cancer cells requires mitochondrial cyclophilin-D-p53 signaling. Biochem Biophys Res Commun 437:526–531. doi:10.1016/j.bbrc.2013.06.103

    Article  CAS  Google Scholar 

  • Chiara F, Castellaro D, Marin O, et al. (2008) Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PLoS One 3:e1852. doi:10.1371/journal.pone.0001852

    Article  CAS  Google Scholar 

  • Cho T-H, Aguettaz P, Campuzano O, et al. (2013) Pre- and post-treatment with cyclosporine a in a rat model of transient focal cerebral ischaemia with multimodal MRI screening. Int J Stroke 8:669–674. doi:10.1111/j.1747-4949.2012.00849.x

    Article  Google Scholar 

  • Clarke SJ, Khaliulin I, Das M, et al. (2008) Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res 102:1082–1090. doi:10.1161/CIRCRESAHA.107.167072

    Article  CAS  Google Scholar 

  • Claros MG, Vincens P (1996) Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241:779–786

    Article  CAS  Google Scholar 

  • Connern CP, Halestrap AP (1994) Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel. Biochem J 302(Pt 2):321–324

    Article  CAS  Google Scholar 

  • Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8:939–944. doi:10.1038/sj.embor.7401062

    Article  CAS  Google Scholar 

  • Crofts AR, Chappell JB (1965) Calcium ion accumulation and volume changes of isolated liver mitochondria. Reversal of calcium ion-induced swelling. Biochem J 95:387–392

    Article  CAS  Google Scholar 

  • Crompton M, Costi A (1988) Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. A potential mechanism for mitochondrial dysfunction during cellular Ca2+ overload. Eur J Biochem 178:489–501

    Article  CAS  Google Scholar 

  • Crompton M, Künzi M, Carafoli E (1977) The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur J Biochem 79:549–558

    Article  CAS  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

    CAS  Google Scholar 

  • Csordás G, Golenár T, Seifert EL, et al. (2013) MICU1 controls both the threshold and cooperative Activationof the mitochondrial Ca. Cell Metab 17:976–987. doi:10.1016/j.cmet.2013.04.020

    Article  CAS  Google Scholar 

  • Das AM, Harris DA (1990) Control of mitochondrial ATP synthase in heart cells: inactive to active transitions caused by beating or positive inotropic agents. Cardiovasc Res 24:411–417

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • De Stefani D, Raffaello A, Teardo E, et al. (2012) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340. doi:10.1038/nature10230

    Article  CAS  Google Scholar 

  • De Stefani D, Rizzuto R, Pozzan T (2013) Enjoy the trip: calcium in mitochondria back and forth. Annu Rev Biochem 85:annurev–biochem–060614–034216–32. doi: 10.1146/annurev-biochem-060614-034216

  • Ding Y, Fang H, Shang W, et al. (2015) Mitoflash altered by metabolic stress in insulin-resistant skeletal muscle. J Mol Med 93:1119–1130. doi:10.1007/s00109-015-1278-y

    Article  CAS  Google Scholar 

  • Du H, Guo L, Zhang W, et al. (2011) Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol Aging 32:398–406. doi:10.1016/j.neurobiolaging.2009.03.003

    Article  CAS  Google Scholar 

  • Elrod JW, Wong R, Mishra S, et al. (2010) Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J Clin Invest 120:3680–3687. doi:10.1172/JCI43171

    Article  CAS  Google Scholar 

  • Feldkamp T, Park JS, Pasupulati R, et al. (2009) Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation. Am J Physiol Renal Physiol 297:F1632–F1646. doi:10.1152/ajprenal.00422.2009

    Article  CAS  Google Scholar 

  • Feng J, Lucchinetti E, Ahuja P, et al. (2005) Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology 103:987–995

    Article  CAS  Google Scholar 

  • Feng Y, Xia Y, Yu G, et al. (2013) Cleavage of GSK-3β by calpain counteracts the inhibitory effect of Ser9 phosphorylation on GSK-3β activity induced by H 2O 2. J Neurochem 126:234–242. doi:10.1111/jnc.12285

    Article  CAS  Google Scholar 

  • Feniouk BA, Yoshida M (2008) Regulatory mechanisms of proton-translocating F(O)F (1)-ATP synthase. Results Probl Cell Differ 45:279–308. doi:10.1007/400_2007_043

    Article  CAS  Google Scholar 

  • Fournier N, Ducet G, Crevat A (1987) Action of cyclosporine on mitochondrial calcium fluxes. J Bioenerg Biomembr 19:297–303

    Article  CAS  Google Scholar 

  • Gelb BD, Adams V, Jones SN, et al. (1992) Targeting of hexokinase 1 to liver and hepatoma mitochondria. Proc Natl Acad Sci U S A 89:202–206

    Article  CAS  Google Scholar 

  • Ghafourifar P, Cadenas E (2005) Mitochondrial nitric oxide synthase. Trends Pharmacol Sci 26:190–195. doi:10.1016/j.tips.2005.02.005

    Article  CAS  Google Scholar 

  • Gill RS, Manouchehri N, Lee T-F, et al. (2012) Cyclosporine treatment improves mesenteric perfusion and attenuates necrotizing enterocolitis (NEC)-like intestinal injury in asphyxiated newborn piglets during reoxygenation. Intensive Care Med 38:482–490. doi:10.1007/s00134-011-2436-5

    Article  CAS  Google Scholar 

  • Giorgio V, Bisetto E, Soriano ME, et al. (2009) Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988. doi:10.1074/jbc.M109.020115

    Article  CAS  Google Scholar 

  • Giorgio V, Stockum von S, Antoniel M, et al. (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci 110:5887–5892. doi:10.1073/pnas.1217823110

    Article  CAS  Google Scholar 

  • Gomez L, Paillard M, Thibault H, et al. (2008) Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation 117:2761–2768. doi:10.1161/CIRCULATIONAHA.107.755066

    Article  CAS  Google Scholar 

  • Goñi-Oliver P, Lucas JJ, Avila J, Hernandez F (2007) N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation. J Biol Chem 282:22406–22413. doi:10.1074/jbc.M702793200

    Article  CAS  Google Scholar 

  • Grijalba MT, Vercesi AE, Schreier S (1999) Ca2 + −induced increased lipid packing and domain formation in submitochondrial particles. A possible early step in the mechanism of Ca2 + −stimulated generation of reactive oxygen species by the respiratory chain. Biochemistry 38:13279–13287. doi:10.1021/bi9828674

    Article  CAS  Google Scholar 

  • Gunter TE, Pfeiffer DR (1990) Mechanisms by which mitochondria transport calcium. Am J Phys 258:C755–C786

    CAS  Google Scholar 

  • Gutiérrez-Aguilar M, Douglas DL, Gibson AK, et al. (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

    Article  CAS  Google Scholar 

  • Hackenbrock CR, Caplan AI (1969) Ion-induced ultrastructural transformations in isolated mitochondria. The energized uptake of calcium The Journal of Cell Biology 42:221–234

    CAS  Google Scholar 

  • Hafner AV, Dai J, Gomes AP, et al. (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2:914–923

    Article  CAS  Google Scholar 

  • Halestrap AP (1991) Calcium-dependent opening of a non-specific pore in the mitochondrial inner membrane is inhibited at pH values below 7. Implications for the protective effect of low pH against chemical and hypoxic cell damage. Biochem J 278(Pt 3):715–719

    Article  CAS  Google Scholar 

  • Halestrap AP (2010) A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem Soc Trans 38:841–860

    Article  CAS  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  CAS  Google Scholar 

  • Halestrap AP, Richardson AP (2015) The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol 78:129–141. doi:10.1016/j.yjmcc.2014.08.018

    Article  CAS  Google Scholar 

  • Halestrap AP, Woodfield KY, Connern CP (1997) Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem 272:3346–3354

    Article  CAS  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. doi:10.1161/01.CIR.0000126294.81407.7D

    Article  CAS  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  CAS  Google Scholar 

  • Haworth RA, Hunter DR (2000) Control of the mitochondrial permeability transition pore by high-affinity ADP binding at the ADP/ATP translocase in permeabilized mitochondria. J Bioenerg Biomembr 32:91–96

    Article  CAS  Google Scholar 

  • Hernando V, Inserte J, Sartório CL, et al. (2010) Calpain translocation and activation as pharmacological targets during myocardial ischemia/reperfusion. J Mol Cell Cardiol 49:271–279. doi:10.1016/j.yjmcc.2010.02.024

    Article  CAS  Google Scholar 

  • Hoffmann B, Stöckl A, Schlame M, et al. (1994) The reconstituted ADP/ATP carrier activity has an absolute requirement for cardiolipin as shown in cysteine mutants. J Biol Chem 269:1940–1944

    CAS  Google Scholar 

  • Hom JR, Gewandter JS, Michael L, et al. (2007) Thapsigargin induces biphasic fragmentation of mitochondria through calcium-mediated mitochondrial fission and apoptosis. J Cell Physiol 212:498–508. doi:10.1002/jcp.21051

    Article  CAS  Google Scholar 

  • Hom J, Yu T, Yoon Y, et al. (2010) Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes. Biochim Biophys Acta 1797:913–921. doi:10.1016/j.bbabio.2010.03.018

    Article  CAS  Google Scholar 

  • Hom JR, Quintanilla RA, Hoffman DL, et al. (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

    Article  CAS  Google Scholar 

  • Hool LC, Corry B (2007) Redox control of calcium channels: from mechanisms to therapeutic opportunities. Antioxid Redox Signal 9:409–435. doi:10.1089/ars.2006.1446

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Hunter DR, Haworth RA (1979) The Ca2 + −induced membrane transition in mitochondria. I The protective mechanisms Archives of Biochemistry and Biophysics 195:453–459

    Article  CAS  Google Scholar 

  • Hunter DR, Haworth RA, Southard JH (1976) Relationship between configuration, function, and permeability in calcium-treated mitochondria. J Biol Chem 251:5069–5077

    CAS  Google Scholar 

  • Hurst S, Gomez L, Jhun B, et al (2015) Truncation of GSK-3β in Cardiac Mitochondria is the Master Switch of the mPTP

  • Ichas F, Jouaville LS, Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89:1145–1153

    Article  CAS  Google Scholar 

  • Inoue T, Yoshida Y, Isaka Y, Tagawa K (1993) Isolation of mitochondrial cyclophilin from bovine heart. Biochem Biophys Res Commun 190:857–863. doi:10.1006/bbrc.1993.1127

    Article  CAS  Google Scholar 

  • Inserte J, Garcia-Dorado D, Hernando V, et al. (2006) Ischemic preconditioning prevents calpain-mediated impairment of Na+/K + −ATPase activity during early reperfusion. Cardiovasc Res 70:364–373. doi:10.1016/j.cardiores.2006.02.017

    Article  CAS  Google Scholar 

  • Inserte J, Barba I, Hernando V, Garcia-Dorado D (2009) Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium. Cardiovasc Res 81:116–122. doi:10.1093/cvr/cvn260

    Article  CAS  Google Scholar 

  • Javadov SA, Clarke S, Das M, et al. (2003) Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol 549:513–524. doi:10.1113/jphysiol.2003.034231

    Article  CAS  Google Scholar 

  • Jekabsone A, Ivanoviene L, Brown GC, Borutaite V (2003) Nitric oxide and calcium together inactivate mitochondrial complex I and induce cytochrome c release. J Mol Cell Cardiol 35:803–809

    Article  CAS  Google Scholar 

  • Jiang D, Zhao L, Clapham DE (2009) Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326:144–147. doi:10.1126/science.1175145

    Article  CAS  Google Scholar 

  • Jin N, Yin X, Yu D, et al. (2015) Truncation and activation of GSK-3β by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer's disease. Sci Rep 5:8187. doi:10.1038/srep08187

    Article  CAS  Google Scholar 

  • Johnson KM, Chen X, Boitano A, et al. (2005) Identification and validation of the mitochondrial F1F0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423. Chem Biol 12:485–496. doi:10.1016/j.chembiol.2005.02.012

    Article  CAS  Google Scholar 

  • Joiner M-LA, Koval OM, Li J, et al. (2012) CaMKII determines mitochondrial stress responses in heart. Nature 491:269–273. doi:10.1038/nature11444

    Article  CAS  Google Scholar 

  • Jou M-J (2011) Melatonin preserves the transient mitochondrial permeability transition for protection during mitochondrial Ca2+ stress in astrocyte. J Pineal Res 50:427–435. doi:10.1111/j.1600-079X.2011.00861.x

    Article  CAS  Google Scholar 

  • Juhaszova M, Zorov DB, Kim S-H, et al. (2004) Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113:1535–1549. doi:10.1172/JCI19906

    Article  CAS  Google Scholar 

  • Jung S, Yang H, Kim BS, et al. (2012) The immunosuppressant cyclosporin a inhibits recurrent seizures in an experimental model of temporal lobe epilepsy. Neurosci Lett 529:133–138. doi:10.1016/j.neulet.2012.08.087

    Article  CAS  Google Scholar 

  • Kadenbach B, Mende P, Kolbe HV, et al. (1982) The mitochondrial phosphate carrier has an essential requirement for cardiolipin. FEBS Lett 139:109–112

    Article  CAS  Google Scholar 

  • Kar P, Samanta K, Shaikh S, et al. (2010) Archives of biochemistry and biophysics. Arch Biochem Biophys 495:1–7. doi:10.1016/j.abb.2009.12.020

    Article  CAS  Google Scholar 

  • Karch J, Molkentin JD (2012) Is p53 the long-sought molecular trigger for cyclophilin D-regulated mitochondrial permeability transition pore formation and necrosis? Circ Res 111:1258–1260. doi:10.1161/CIRCRESAHA.112.280990

    Article  CAS  Google Scholar 

  • Karch J, Kwong JQ, Burr AR, et al. (2013) Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice. Elife 2:e00772. doi:10.7554/eLife.00772

    Article  Google Scholar 

  • Khalil PN, Neuhof C, Huss R, et al. (2005) Calpain inhibition reduces infarct size and improves global hemodynamics and left ventricular contractility in a porcine myocardial ischemia/reperfusion model. Eur J Pharmacol 528:124–131. doi:10.1016/j.ejphar.2005.10.032

    Article  CAS  Google Scholar 

  • Khaliulin I, Schwalb H, Wang P, et al. (2004) Preconditioning improves postischemic mitochondrial function and diminishes oxidation of mitochondrial proteins. Free Radic Biol Med 37:1–9. doi:10.1016/j.freeradbiomed.2004.04.017

    Article  CAS  Google Scholar 

  • Khaliulin I, Clarke SJ, Lin H, et al. (2007) Temperature preconditioning of isolated rat hearts--a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore. J Physiol 581:1147–1161. doi:10.1113/jphysiol.2007.130369

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Kinnally KW, Zorov DB, Antonenko YN, et al. (1993) Mitochondrial benzodiazepine receptor linked to inner membrane ion channels by nanomolar actions of ligands. Proc Natl Acad Sci U S A 90:1374–1378

    Article  CAS  Google Scholar 

  • Kinnally KW, Peixoto PM, Ryu S-Y, 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

    Article  CAS  Google Scholar 

  • Klöhn P-C, Soriano ME, Irwin W, et al. (2003) Early resistance to cell death and to onset of the mitochondrial permeability transition during hepatocarcinogenesis with 2-acetylaminofluorene. Proc Natl Acad Sci U S A 100:10014–10019. doi:10.1073/pnas.1633614100

    Article  CAS  Google Scholar 

  • Kohr MJ, Aponte AM, Sun J, et al. (2011a) Characterization of potential S-nitrosylation sites in the myocardium. AJP: Heart and Circulatory Physiology 300:H1327–H1335. doi:10.1152/ajpheart.00997.2010

    CAS  Google Scholar 

  • Kohr MJ, Sun J, Aponte A, et al. (2011b) Simultaneous measurement of protein oxidation and S-nitrosylation during preconditioning and ischemia/reperfusion injury with resin-assisted capture. Circ Res 108:418–426. doi:10.1161/CIRCRESAHA.110.232173

    Article  CAS  Google Scholar 

  • Kokoszka JE, Waymire KG, Levy SE, et al. (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465. doi:10.1038/nature02229

    Article  CAS  Google Scholar 

  • Konukoglu D, Taşci I, Cetinkale O (1998) Effects of cyclosporin a and ibuprofen on liver ischemia-reperfusion injury in the rat. Clin Chim Acta 275:1–8

    Article  CAS  Google Scholar 

  • Kwong JQ, Molkentin JD (2015) Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab 21:206–214. doi:10.1016/j.cmet.2014.12.001

    Article  CAS  Google Scholar 

  • Kwong JQ, Davis J, Baines CP, et al. (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

    Article  CAS  Google Scholar 

  • Lacza Z, Pankotai E, Csordás A, et al. (2006) Mitochondrial NO and reactive nitrogen species production: does mtNOS exist? Nitric Oxide 14:162–168. doi:10.1016/j.niox.2005.05.011

    Article  CAS  Google Scholar 

  • Lehninger AL (1959) Reversal of various types of mitochondrial swelling by adenosine triphosphate. J Biol Chem 234:2465–2471

    CAS  Google Scholar 

  • Leung AWC, Varanyuwatana P, Halestrap AP (2008) The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem 283:26312–26323. doi:10.1074/jbc.M805235200

    Article  CAS  Google Scholar 

  • Linard D, Kandlbinder A, Degand H, et al. (2009) Redox characterization of human cyclophilin D: identification of a new mammalian mitochondrial redox sensor? Arch Biochem Biophys 491:39–45. doi:10.1016/j.abb.2009.09.002

    Article  CAS  Google Scholar 

  • Lu X, Kwong J, Molkentin JD, Bers DM (2015) Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings. Circ Res CIRCRESAHA.115.308093–16. doi: 10.1161/CIRCRESAHA.115.308093

  • Luongo TS, Lambert JP, Yuan A, et al (2015) The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. CellReports 12:23–34. doi: 10.1016/j.celrep.2015.06.017

  • Ma S, Liu S, Huang Q, et al. (2012) Site-specific phosphorylation protects glycogen synthase kinase-3 from calpain-mediated truncation of its N and C termini. J Biol Chem 287:22521–22532. doi:10.1074/jbc.M111.321349

    Article  CAS  Google Scholar 

  • Maekawa A, Lee J-K, Nagaya T, et al. (2003) Overexpression of calpastatin by gene transfer prevents troponin I degradation and ameliorates contractile dysfunction in rat hearts subjected to ischemia/reperfusion. J Mol Cell Cardiol 35:1277–1284

    Article  CAS  Google Scholar 

  • Mallilankaraman K, Cárdenas C, Doonan PJ, et al. (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343. doi:10.1038/ncb2622

    Article  CAS  Google Scholar 

  • Markevich NI, Hoek JB (2015) Computational modeling analysis of mitochondrial superoxide production under varying substrate conditions and upon inhibition of different segments of the electron transport chain. Biochim Biophys Acta 1847:656–679. doi:10.1016/j.bbabio.2015.04.005

    Article  CAS  Google Scholar 

  • Martin LJ, Fancelli D, Wong M, et al. (2014a) GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis. Front Cell Neurosci 8:433. doi:10.3389/fncel.2014.00433

    Google Scholar 

  • Martin LJ, Semenkow S, Hanaford A, Wong M (2014b) Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice. Neurobiol Aging 35:1132–1152. doi:10.1016/j.neurobiolaging.2013.11.008

    Article  CAS  Google Scholar 

  • Marzo I, Brenner C, Zamzami N, et al. (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 187:1261–1271

    Article  CAS  Google Scholar 

  • Massari S, Azzone GF (1972) The equivalent pore radius of intact and damaged mitochondria and the mechanism of active shrinkage. Biochim Biophys Acta 283:23–29

    Article  CAS  Google Scholar 

  • McCormack JG, Denton RM (1989) The role of Ca2+ ions in the regulation of intramitochondrial metabolism and energy production in rat heart. Mol Cell Biochem 89:121–125

    CAS  Google Scholar 

  • McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425

    CAS  Google Scholar 

  • McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A 89:3170–3174

    Article  CAS  Google Scholar 

  • Michels G, Khan IF, Endres-Becker J, et al. (2009) Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119:2435–2443. doi:10.1161/CIRCULATIONAHA.108.835389

    Article  CAS  Google Scholar 

  • Miura T, Tanno M (2010) Mitochondria and GSK-3β in cardioprotection against ischemia/reperfusion injury. Cardiovasc Drugs Ther 24:255–263. doi:10.1007/s10557-010-6234-z

    Article  CAS  Google Scholar 

  • Miyamoto S, Murphy AN, Brown JH (2008) Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 15:521–529. doi:10.1038/sj.cdd.4402285

    Article  CAS  Google Scholar 

  • Mizuta K, Ohmori M, Miyashita F, et al. (1999) Effect of pretreatment with FTY720 and cyclosporin on ischaemia-reperfusion injury of the liver in rats. J Pharm Pharmacol 51:1423–1428

    Article  CAS  Google Scholar 

  • Moody BF, Calvert JW (2011) Emergent role of gasotransmitters in ischemia-reperfusion injury. Med Gas Res 1:3. doi:10.1186/2045-9912-1-3

    Article  CAS  Google Scholar 

  • Morciano G, Giorgi C, Bonora M, et al. (2015) Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. J Mol Cell Cardiol 78:142–153. doi:10.1016/j.yjmcc.2014.08.015

    Article  CAS  Google Scholar 

  • Muller FL, Roberts AG, Bowman MK, Kramer DM (2003) Architecture of the Qo site of the cytochrome bc1 complex probed by superoxide production. Biochemistry 42:6493–6499. doi:10.1021/bi0342160

    Article  CAS  Google Scholar 

  • Nakagawa T, Shimizu S, Watanabe T, et al. (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658. doi:10.1038/nature03317

    Article  CAS  Google Scholar 

  • Nguyen TT, Stevens MV, Kohr M, et al. (2011) Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore. J Biol Chem 286:40184–40192. doi:10.1074/jbc.M111.243469

    Article  CAS  Google Scholar 

  • Ni R, Zheng D, Xiong S, et al (2015) Mitochondrial calpain-1 disrupts ATP synthase and induces superoxide generation in type-1 diabetic hearts: a novel mechanism contributing to diabetic cardiomyopathy. Diabetes db150963. doi: 10.2337/db15-0963

  • Nicholls DG, Chalmers S (2004) The integration of mitochondrial calcium transport and storage. J Bioenerg Biomembr 36:277–281. doi:10.1023/B:JOBB.0000041753.52832.f3

    Article  CAS  Google Scholar 

  • Nicolli A, Petronilli V, Bernardi P (1993) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by matrix pH. Evidence that the pore open-closed probability is regulated by reversible histidine protonation Biochemistry 32:4461–4465

    CAS  Google Scholar 

  • Novgorodov SA, Gudz TI, Brierley GP, Pfeiffer DR (1994) Magnesium ion modulates the sensitivity of the mitochondrial permeability transition pore to cyclosporin a and ADP. Arch Biochem Biophys 311:219–228

    Article  CAS  Google Scholar 

  • Oess S, Icking A, Fulton D, et al. (2006) Subcellular targeting and trafficking of nitric oxide synthases. Biochem J 396:401–409. doi:10.1042/BJ20060321

    Article  CAS  Google Scholar 

  • Ong S-B, Subrayan S, Lim SY, et al. (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022. doi:10.1161/CIRCULATIONAHA.109.906610

    Article  CAS  Google Scholar 

  • Ott M, Robertson JD, Gogvadze V, et al. (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A 99:1259–1263. doi:10.1073/pnas.241655498

    Article  CAS  Google Scholar 

  • O-Uchi J, Jhun BS, Xu S, et al. (2014a) Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter. Antioxid Redox Signal 21:863–879. doi:10.1089/ars.2013.5394

    Article  CAS  Google Scholar 

  • O-Uchi J, Ryu S-Y, Jhun BS, et al. (2014b) Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling. Antioxid Redox Signal 21:987–1006. doi:10.1089/ars.2013.5681

    Article  CAS  Google Scholar 

  • Out TA, Kemp A, Souverijn JH (1971) The effect of bongkrekic acid on the Ca 2+ − stimulated oxidation in rat-liver mitochondria and its relation to the efflux of intramitochondrial adenine nucleotides. Biochim Biophys Acta 245:299–304

    Article  CAS  Google Scholar 

  • Ozaki T, Tomita H, Tamai M, Ishiguro S-I (2007) Characteristics of mitochondrial calpains. J Biochem 142:365–376. doi:10.1093/jb/mvm143

    Article  CAS  Google Scholar 

  • Ozaki T, Yamashita T, Ishiguro S-I (2009) Mitochondrial m-calpain plays a role in the release of truncated apoptosis-inducing factor from the mitochondria. Biochim Biophys Acta 1793:1848–1859. doi:10.1016/j.bbamcr.2009.10.002

    Article  CAS  Google Scholar 

  • Packer MA, Scarlett JL, Martin SW, Murphy MP (1997) Induction of the mitochondrial permeability transition by peroxynitrite. Biochem Soc Trans 25:909–914

    Article  CAS  Google Scholar 

  • Palty R, Silverman WF, Hershfinkel M, et al. (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci 107:436–441. doi:10.1073/pnas.0908099107

    Article  CAS  Google Scholar 

  • Park JS, Pasupulati R, Feldkamp T, et al. (2011) Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury. Am J Physiol Renal Physiol 301:F134–F150. doi:10.1152/ajprenal.00033.2011

    Article  CAS  Google Scholar 

  • Pasdois P, Parker JE, Griffiths EJ, Halestrap AP (2011) The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia. Biochem J 436:493–505. doi:10.1042/BJ20101957

    Article  CAS  Google Scholar 

  • 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–e005645. doi:10.1161/JAHA.112.005645

    Google Scholar 

  • Pastorino JG (2005) Activation of glycogen synthase kinase 3 disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent Anion Channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65:10545–10554. doi:10.1158/0008-5472.CAN-05-1925

    Article  CAS  Google Scholar 

  • Pastorino JG, Hoek JB (2003) Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem 10:1535–1551

    Article  CAS  Google Scholar 

  • Pavlov E, Zakharian E, Bladen C, et al. (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

    Article  CAS  Google Scholar 

  • Perez-Campo R, López-Torres M, Cadenas S, et al. (1998) The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol B, Biochem Syst Environ Physiol 168:149–158

    Article  CAS  Google Scholar 

  • Pestana CR, Silva CHTP, Pardo-Andreu GL, et al. (2009) Ca(2+) binding to c-state of adenine nucleotide translocase (ANT)-surrounding cardiolipins enhances (ANT)-Cys(56) relative mobility: a computational-based mitochondrial permeability transition study. Biochim Biophys Acta 1787:176–182. doi:10.1016/j.bbabio.2008.12.013

    Article  CAS  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  CAS  Google Scholar 

  • Petronilli V, Miotto G, Canton M, et al. (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

    Article  CAS  Google Scholar 

  • Piot C, Croisille P, Staat P, et al. (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481. doi:10.1056/NEJMoa071142

    Article  CAS  Google Scholar 

  • Pivovarova NB, Andrews SB (2010) Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J 277:3622–3636. doi:10.1111/j.1742-4658.2010.07754.x

    Article  CAS  Google Scholar 

  • Pozzan T, Bragadin M, Azzone GF (1977) Disequilibrium between steady-state Ca2+ accumulation ratio and membrane potential in mitochondria. Pathway and role of Ca2+ efflux. Biochemistry 16:5618–5625

    Article  CAS  Google Scholar 

  • Quatresous E, Legrand C, Pouvreau S (2012) Mitochondria-targeted cpYFP: pH or superoxide sensor? The Journal of General Physiology 140:567–570. doi:10.1085/jgp.201210863

    Article  CAS  Google Scholar 

  • Quintanilla RA, Jin YN, Bernhardi von R, Johnson GVW (2013) Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Mol Neurodegener 8:45. doi:10.1186/1750-1326-8-45

    Article  CAS  Google Scholar 

  • Radi R, Rodriguez M, Castro L, Telleri R (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308:89–95. doi:10.1006/abbi.1994.1013

    Article  CAS  Google Scholar 

  • Rapizzi E, Pinton P, Szabadkai G, et al. (2002) Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol 159:613–624. doi:10.1083/jcb.200205091

    Article  CAS  Google Scholar 

  • Rasola A, Sciacovelli M, Chiara F, et al. (2010) Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci 107:726–731. doi:10.1073/pnas.0912742107

    Article  CAS  Google Scholar 

  • Roberts DJ, Tan-Sah VP, Smith JM, Miyamoto S (2013) Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem 288:23798–23806. doi:10.1074/jbc.M113.482026

    Article  CAS  Google Scholar 

  • Rottenberg H, Marbach M (1990) Regulation of Ca 2+ transport in brain mitochondria. II. The mechanism of the adenine nucleotides enhancement of Ca 2+ uptake and retention. Biochimica et Biophysica Acta (BBA)- … 1016:87–98. doi: 10.1016/0005-2728(90)90010-2

  • Sancak Y, Markhard AL, Kitami T, et al. (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379–1382. doi:10.1126/science.1242993

    Article  CAS  Google Scholar 

  • Santos CXC, Anilkumar N, Zhang M, et al. (2011) Redox signaling in cardiac myocytes. Free Radic Biol Med 50:777–793. doi:10.1016/j.freeradbiomed.2011.01.003

    Article  CAS  Google Scholar 

  • Savino C, Pelicci P, Giorgio M (2013) The P66Shc/mitochondrial permeability transition pore pathway determines neurodegeneration. Oxidative Med Cell Longev 2013:719407–719407. doi:10.1155/2013/719407

    Article  CAS  Google Scholar 

  • Saxton NE, Barclay JL, Clouston AD, Fawcett J (2002) Cyclosporin a pretreatment in a rat model of warm ischaemia/reperfusion injury. J Hepatol 36:241–247

    Article  CAS  Google Scholar 

  • Scarlett JL, Packer MA, Porteous CM, Murphy MP (1996) Alterations to glutathione and nicotinamide nucleotides during the mitochondrial permeability transition induced by peroxynitrite. Biochem Pharmacol 52:1047–1055. doi:10.1016/0006-2952(96)99426-5

    Article  CAS  Google Scholar 

  • Schinzel AC, Takeuchi O, Huang Z, et al. (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. doi:10.1073/pnas.0505294102

    Article  CAS  Google Scholar 

  • Schwarzländer M, Wagner S, Ermakova YG, et al. (2014) The “mitoflash” probe cpYFP does not respond to superoxide. Nature 514:E12–E14. doi:10.1038/nature13858

    Article  CAS  Google Scholar 

  • Shanmughapriya S, Rajan S, Hoffman NE, et al. (2015) SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore. Mol Cell:1–41. doi:10.1016/j.molcel.2015.08.009

  • Shao H, Chou J, Baty CJ, et al. (2006) Spatial localization of m-calpain to the plasma membrane by phosphoinositide biphosphate binding during epidermal growth factor receptor-mediated activation. Mol Cell Biol 26:5481–5496. doi:10.1128/MCB.02243-05

    Article  CAS  Google Scholar 

  • Shen E-Z, Song C-Q, Lin Y, et al. (2014) Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans. Nature 508:128–132. doi:10.1038/nature13012

    Article  CAS  Google Scholar 

  • Shiga Y, Onodera H, Matsuo Y, Kogure K (1992) Cyclosporin a protects against ischemia-reperfusion injury in the brain. Brain Res 595:145–148

    Article  CAS  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. doi:10.1038/20959

    Article  CAS  Google Scholar 

  • Shintani-Ishida K, Yoshida K-I (2015) Mitochondrial m-calpain opens the mitochondrial permeability transition pore in ischemia-reperfusion. Int J Cardiol 197:26–32. doi:10.1016/j.ijcard.2015.06.010

    Article  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. doi:10.1242/jcs.073502

    Article  CAS  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. doi:10.1242/jcs.061846

    Article  CAS  Google Scholar 

  • Šileikytė J, Blachly-Dyson E, Sewell R, et al. (2014) Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (translocator protein of 18 kDa (TSPO)). J Biol Chem 289:13769–13781. doi:10.1074/jbc.M114.549634

    Article  CAS  Google Scholar 

  • Soda Y, El-Assal ON, Yu L, Nagasue N (1999) Suppressed endothelin-1 production by FK506 and cyclosporin a in ischemia/reperfusion of rat small intestine. Surgery 125:23–32

    Article  CAS  Google Scholar 

  • Sohal RS, Allen RG (1985) Relationship between metabolic rate, free radicals, differentiation and aging: a unified theory. Basic Life Sci 35:75–104

    CAS  Google Scholar 

  • Solesio ME, Demirkhanyan L, Zakharian E, Pavlov EV (2016a) Contribution of inorganic polyphosphate towards regulation of mitochondrial free calcium. BBA - General Subjects 1860:1317–1325. doi:10.1016/j.bbagen.2016.03.020

    Article  CAS  Google Scholar 

  • 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 44:7–12. doi:10.1042/BST20150206

    Article  CAS  Google Scholar 

  • Song Y-H, Cho H, Ryu S-Y, et al. (2010) L-type Ca(2+) channel facilitation mediated by H(2)O(2)-induced activation of CaMKII in rat ventricular myocytes. J Mol Cell Cardiol 48:773–780. doi:10.1016/j.yjmcc.2009.10.020

    Article  CAS  Google Scholar 

  • Song Y-H, Choi E, Park S-H, et al. (2011) Sustained CaMKII activity mediates transient oxidative stress-induced long-term facilitation of L-type Ca(2+) current in cardiomyocytes. Free Radic Biol Med 51:1708–1716. doi:10.1016/j.freeradbiomed.2011.07.022

    Article  CAS  Google Scholar 

  • Sorimachi H, Ono Y (2012) Regulation and physiological roles of the calpain system in muscular disorders. Cardiovasc Res 96:11–22. doi:10.1093/cvr/cvs157

    Article  CAS  Google Scholar 

  • Sparagna GC, Gunter KK, Sheu SS, Gunter TE (1995) Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode J Biol Chem 270:27510–27515

    CAS  Google Scholar 

  • St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790. doi:10.1074/jbc.M207217200

    Article  CAS  Google Scholar 

  • Sun J, Murphy E (2010) Protein S-nitrosylation and cardioprotection. Circ Res 106:285–296. doi:10.1161/CIRCRESAHA.109.209452

    Article  CAS  Google Scholar 

  • Sun J, Steenbergen C, Murphy E (2006) S-nitrosylation: NO-related redox signaling to protect against oxidative stress. Antioxid Redox Signal 8:1693–1705. doi:10.1089/ars.2006.8.1693

    Article  CAS  Google Scholar 

  • Sun J, Morgan M, Shen R-F, et al. (2007) Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport. Circ Res 101:1155–1163. doi:10.1161/CIRCRESAHA.107.155879

    Article  CAS  Google Scholar 

  • Sundberg TB, Swenson L, Wahl DR, et al. (2009) Apoptotic signaling activated by modulation of the F0F1-ATPase: implications for selective killing of autoimmune lymphocytes. J Pharmacol Exp Ther 331:437–444. doi:10.1124/jpet.109.156422

    Article  CAS  Google Scholar 

  • Szabo I, Zoratti M (1993) The mitochondrial permeability transition pore may comprise VDAC molecules. I. Binary structure and voltage dependence of the pore. FEBS Lett 330:201–205

    Article  CAS  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

    CAS  Google Scholar 

  • Tan W, Colombini M (2007) VDAC closure increases calcium ion flux. Biochim Biophys Acta Biomembr 1768:2510–2515. doi:10.1016/j.bbamem.2007.06.002

    Article  CAS  Google Scholar 

  • Tanno M, Kuno A, Ishikawa S, et al (2014) Translocation of GSK-3β, a Trigger of Permeability Transition, Is Kinase Activity-dependent and Mediated by Interaction with VDAC2. J Biol Chem 289:jbc.M114.563924–29296. doi: 10.1074/jbc.M114.563924

  • Tanveer A, Virji S, Andreeva L, et al. (1996) Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur J Biochem 238:166–172

    Article  CAS  Google Scholar 

  • Tong H, Imahashi K, Steenbergen C, Murphy E (2002) Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res 90:377–379

    Article  CAS  Google Scholar 

  • Traba J, Del Arco A, Duchen MR, et al. (2012) SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering. Cell Death Differ 19:650–660. doi:10.1038/cdd.2011.139

    Article  CAS  Google Scholar 

  • Trachootham D, Lu W, Ogasawara MA, et al. (2008) Redox regulation of cell survival. Antioxid Redox Signal 10:1343–1374. doi:10.1089/ars.2007.1957

    Article  CAS  Google Scholar 

  • Turrens JF (1997) Superoxide production by the mitochondrial respiratory chain. Biosci Rep 17:3–8

    Article  CAS  Google Scholar 

  • Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344. doi:10.1113/jphysiol.2003.049478

    Article  CAS  Google Scholar 

  • Vainio H, Mela L, Chance B (1970) Energy dependent bivalent cation translocation in rat liver mitochondria. Eur J Biochem 12:387–391

    Article  CAS  Google Scholar 

  • Valko M, Leibfritz D, Moncol J, et al. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84. doi:10.1016/j.biocel.2006.07.001

    Article  CAS  Google Scholar 

  • Van Walraven HS, Scholts MJC, Zakharov SD, et al. (2002) pH-dependent Ca2+ binding to the F0 c-subunit affects proton translocation of the ATP synthase from Synechocystis 6803. J Bioenerg Biomembr 34:455–464

    Article  CAS  Google Scholar 

  • Varanyuwatana P, Halestrap AP (2012) The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. MITOCH 12:120–125. doi:10.1016/j.mito.2011.04.006

    Article  CAS  Google Scholar 

  • Vaseva AV, Marchenko ND, Ji K, et al. (2012) p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149:1536–1548. doi:10.1016/j.cell.2012.05.014

    Article  CAS  Google Scholar 

  • Vega-Naredo I, Loureiro R, Mesquita KA, et al. (2014) Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells. Cell Death Differ 21:1560–1574. doi:10.1038/cdd.2014.66

    Article  CAS  Google Scholar 

  • Verma M, Shulga N, Pastorino JG (2013) Sirtuin-3 modulates Bak- and Bax-dependent apoptosis. J Cell Sci 126:274–288. doi:10.1242/jcs.115188

    Article  CAS  Google Scholar 

  • Wang W, Fang H, Groom L, et al. (2008) Superoxide flashes in single mitochondria. Cell 134:279–290. doi:10.1016/j.cell.2008.06.017

    Article  CAS  Google Scholar 

  • Wei A-C, Liu T, Winslow RL, O'Rourke B (2012) Dynamics of matrix-free Ca2+ in cardiac mitochondria: two components of Ca2+ uptake and role of phosphate buffering. The Journal of General Physiology 139:465–478. doi:10.1085/jgp.201210784

    Article  CAS  Google Scholar 

  • Whelan RS, Konstantinidis K, Wei A-C, et al. (2012) Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci 109:6566–6571. doi:10.1073/pnas.1201608109

    Article  CAS  Google Scholar 

  • Xi J, Wang H, Mueller RA, et al. (2009) Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore. Eur J Pharmacol 604:111–116. doi:10.1016/j.ejphar.2008.12.024

    Article  CAS  Google Scholar 

  • Xie GC, Wilson JE (1988) Rat brain hexokinase: the hydrophobic N-terminus of the mitochondrially bound enzyme is inserted in the lipid bilayer. Arch Biochem Biophys 267:803–810

    Article  CAS  Google Scholar 

  • Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. doi:10.1056/NEJMra071667

    Article  CAS  Google Scholar 

  • Yu T, Sheu S-S, Robotham JL, Yoon Y (2008) Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 79:341–351. doi:10.1093/cvr/cvn104

    Article  CAS  Google Scholar 

  • Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora's box opens. Nat Rev Mol Cell Biol 2:67–71. doi:10.1038/35048073

    Article  CAS  Google Scholar 

  • Zaobornyj T, Ghafourifar P (2012) Strategic localization of heart mitochondrial NOS: a review of the evidence. AJP: Heart and Circulatory Physiology 303:H1283–H1293. doi:10.1152/ajpheart.00674.2011

    CAS  Google Scholar 

  • Zhai P, Sciarretta S, Galeotti J, et al. (2011) Differential roles of GSK-3 during myocardial ischemia and ischemia/reperfusion. Circ Res 109:502–511. doi:10.1161/CIRCRESAHA.111.249532

    Article  CAS  Google Scholar 

  • Zhao L-P, Ji C, Lu P-H, et al. (2013) Oxygen glucose deprivation (OGD)/re-oxygenation-induced in vitro neuronal cell death involves mitochondrial cyclophilin-D/P53 signaling axis. Neurochem Res 38:705–713. doi:10.1007/s11064-013-0968-5

    Article  CAS  Google Scholar 

  • Zhen Y-F, Wang G-D, Zhu L-Q, et al. (2014) P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol 229:1475–1483. doi:10.1002/jcp.24589

    Article  CAS  Google Scholar 

  • Zorov DB, Kinnally KW, Perini S, Tedeschi H (1992) Multiple conductance levels in rat heart inner mitochondrial membranes studied by patch clamping. Biochim Biophys Acta 1105:263–270

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge Jennifer Wilson, for her constructive comments as well as our funding from the National Instute of Health: 2R01HL093671, 1R01HL122124, & 1RO1114760 to S-S. Sheu; T32AA007463 to J. Hoek & S. Hurst, and R01AA018873 to J.Hoek.

Author information

Authors and Affiliations

  1. Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Suite 543D, Philadelphia, PA, 19107, USA

    Stephen Hurst & Shey-Shing Sheu

  2. Mitocare Center for Mitochondria Research, Department of Pathology Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Jan Hoek

Authors
  1. Stephen Hurst
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan Hoek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shey-Shing Sheu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shey-Shing Sheu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hurst, S., Hoek, J. & Sheu, SS. Mitochondrial Ca2+ and regulation of the permeability transition pore. J Bioenerg Biomembr 49, 27–47 (2017). https://doi.org/10.1007/s10863-016-9672-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-016-9672-x

Keywords

Search

Navigation