Skip to main content
SpringerLink
Log in

Induction of unspecific permeabilization of mitochondrial membrane and its role in cell death

  • Reviews
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Mitochondria participate in various vital cellular processes. Violation of their functions can lead to the development of cardiovascular and neurodegenerative diseases and malignancies. One of the key events responsible for mitochondrial damage—induction of Ca2+-dependent mitochondrial permeability transition, due to the opening of a nonspecific pore in the inner mitochondrial membrane. Despite active studies of pore components, its detailed structure has not yet been established. This review analyzes possible constituents and regulators of the pore, the role of the pore in various pathologies, and hypotheses that explain the organization of the pores. Elucidation of these questions can help developing strategies for the treatment of a wide range of pathologies—from Alzheimer and Parkinson’s disease to cancer.

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

Similar content being viewed by others

Abbreviations

OMM:

outer mitochondrial membrane

МРТ:

mitochondrial permeability transition

VDAC:

voltage-dependent anion channel

ANT:

adenine nucleotide translocase

HK:

hexokinase

CK:

creatine kinase

CypD:

cyclophiline D

CsA:

cyclosporine A

ROS:

rective oxygen species

GSK-3β:

Glycogen synthase kinase 3

PiC:

mitochondrial phosphate carrier

TNF-α:

tumor necrosis factor α

PBR:

peripheral benzodiazepine receptor

BKA:

bongkrekic acid

BetA:

betulinic acid

References

  1. Susin S.A. 1996. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J. Exp. Med. 184, 1331–1341.

    Article  CAS  PubMed  Google Scholar 

  2. Marzo I., Brenner C., Zamzami N., Susin S., Beutner G., Brdiczka D., Ré my R., Xie Z.H., Reed J.C., Kroemer G. 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  PubMed  PubMed Central  Google Scholar 

  3. Castedo M., Macho A., Zamzami N., Hirsch T., Marchetti P., Uriel J., Kroemer G. 1995. Mitochondrial perturbations define lymphocytes undergoing apoptotic depletion in vivo. Eur. J. Immunol. 25, 3277–3284.

    Article  CAS  PubMed  Google Scholar 

  4. Lemasters J.J., Nieminen A.-L., Qian T., Trost L.C., Elmore S.P., Nishimura Y., Crowe R. A., Cascio W.E., Bradham C.A., Brenner D.A., Herman B. 1998. The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta. 1366, 177–196.

    Article  CAS  PubMed  Google Scholar 

  5. Marchetti P. 1996. Mitochondrial permeability transition is a central coordinating event of apoptosis. J. Exp. Med. 184, 1155–1160.

    Article  CAS  PubMed  Google Scholar 

  6. Zamzami N. 1996. Mitochondrial control of nuclear apoptosis. J. Exp. Med. 183, 1533–1544.

    Article  CAS  PubMed  Google Scholar 

  7. Goldstein J.C., Waterhouse N.J., Juin P., Evan G.I., Green D.R. 2000. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156–162.

    Article  CAS  PubMed  Google Scholar 

  8. Wei M.C., Lindsten T., Mootha V.K., Weiler S., Gross A., Ashiya M., Thompson C.B., Korsmeyer S.J. 2000. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14, 2060–2071.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Eskes R., Desagher S., Antonsson B., Martinou J.C. 2000. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol. Cell. Biol. 20, 929–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. De Marchi U., Campello S., Szabò I., Tombola F., Martinou J.-C., Zoratti M. 2004. Bax does not directly participate in the Ca2+-induced permeability transition of isolated mitochondria. J. Biol. Chem. 279, 37415–37422.

    Article  PubMed  CAS  Google Scholar 

  11. Campello S., De Marchi U., Szabò I., Tombola F., Martinou J.-C., Zoratti M. 2005. The properties of the mitochondrial megachannel in mitoplasts from human colon carcinoma cells are not influenced by Bax. FEBS Lett. 579, 3695–3700.

    Article  CAS  PubMed  Google Scholar 

  12. Hunter D.R., Haworth R.A. 1979. The Ca2+-induced membrane transition in mitochondria. Arch. Biochem. Biophys. 195, 453–459.

    Article  CAS  PubMed  Google Scholar 

  13. Debatin K.-M., Poncet D., Kroemer G. 2002. Chemotherapy: Targeting the mitochondrial cell death pathway. Oncogene. 21, 8786–8803.

    Article  CAS  PubMed  Google Scholar 

  14. Crompton M. 1999. The mitochondrial permeability transition pore and its role in cell death. Biochem. J. 341, 233–249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brenner C., Grimm S. 2006. The permeability transition pore complex in cancer cell death. Oncogene. 25, 4744–5476.

    Article  CAS  PubMed  Google Scholar 

  16. Kroemer G., Galluzzi L., Brenner C. 2007. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163.

    Article  CAS  PubMed  Google Scholar 

  17. Grimm S., Brdiczka D. 2007. The permeability transition pore in cell death. Apoptosis. 12, 841–855.

    Article  CAS  PubMed  Google Scholar 

  18. Rasola A., Bernardi P. 2007. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis. 12, 815–833.

    Article  CAS  PubMed  Google Scholar 

  19. Chalmers S., Nicholls D.G. 2003. The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J. Biol. Chem. 278, 19062–10970.

    Article  CAS  PubMed  Google Scholar 

  20. Trost L.C., Lemasters J.J. 1996. The mitochondrial permeability transition: A new pathophysiological mechanism for Reye’s syndrome and toxic liver injury. J. Pharmacol. Exp.Ther. 278, 1000–1005.

    CAS  PubMed  Google Scholar 

  21. Lemasters J.J., Theruvath T.P., Zhong Z., Nieminen A.-L. 2009. Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta. 1787, 1395–1401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Scorrano L., Ashiya M., Buttle K., Weiler S., Oakes S.-A., Mannella C.-A., Korsmeyer S.J. 2002. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell. 2, 55–67.

    Article  CAS  PubMed  Google Scholar 

  23. Zoratti M., Szabò I., De Marchi U. 2005. Mitochondrial permeability transitions: How many doors to the house? Biochim. Biophys. Acta. 1706, 40–52.

    Article  CAS  PubMed  Google Scholar 

  24. He L., Lemasters J.J. 2002. Regulated and unregulated mitochondrial permeability transition pores: A new paradigm of pore structure and function? FEBS Lett. 512, 1–7.

    Article  CAS  PubMed  Google Scholar 

  25. Zizi M., Forte M., Blachly-Dyson E., Colombini M. 1994. NADH regulates the gating of VDAC, the mitochondrial outer membrane channel. J. Biol. Chem. 269, 1614–1616.

    CAS  PubMed  Google Scholar 

  26. Gincel D., Zaid H., Shoshan-Barmatz V. 2001. Calcium binding and translocation by the voltage-dependent anion channel: A possible regulatory mechanism in mitochondrial function. Biochem. J. 358, 147–155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gincel D., Shoshan-Barmatz V. 2004. Glutamate interacts with VDAC and modulates opening of the mitochondrial permeability transition pore. J. Bioenerg. Biomembr. 36, 179–186.

    Article  CAS  PubMed  Google Scholar 

  28. Pastorino J.G., Shulga N., Hoek J.B. 2002. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J. Biol. Chem. 277, 7610–7618.

    Article  CAS  PubMed  Google Scholar 

  29. Pastorino J.G., Hoek J.B., Shulga N. 2005. Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res. 65, 10545–10554.

    Article  CAS  PubMed  Google Scholar 

  30. Majewski N., Nogueira V., Bhaskar P., Coy P.E., Skeen J.E., Gottlob K., Chandel N.S., Thompson C.B., Robey R.B., Hay N. 2004. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell. 16, 819–830.

    Article  CAS  PubMed  Google Scholar 

  31. Mathupala S.P., Ko Y.H., Pedersen P.L. 2006. Hexokinase II: Cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene. 25, 4777–4786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shimizu S., Shinohara Y., Tsujimoto Y. 2000. Bax and Bcl-xL independently regulate apoptotic changes of yeast mitochondria that require VDAC but not adenine nucleotide translocator. Oncogene. 19, 4309–4318.

    Article  CAS  PubMed  Google Scholar 

  33. 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  CAS  PubMed  Google Scholar 

  34. Shi Y., Chen J., Weng C., Chen R., Zheng Y., Chen Q., Tang H. 2003. Identification of the protein–protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins. Biochem. Biophys. Res. Commun. 305, 989–996.

    Article  CAS  PubMed  Google Scholar 

  35. Narita M., Shimizu S., Ito T., Chittenden T., Lutz R.J., 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  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shimizu S., Matsuoka Y., Shinohara Y., Yoneda Y., Tsujimoto Y. 2001. Essential role of voltage-dependent anion channel in various forms of apoptosis in mammalian cells. J. Cell Biol. 152, 237–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shimizu S., Konishi a, Kodama T., Tsujimoto Y. 2000. BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc. Natl. Acad. Sci. U. S. A. 97, 3100–3105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rostovtseva T.K., Antonsson B., Suzuki M., Youle R.J., Colombini M., Bezrukov S.M. 2004. Bid, but not Bax, regulates VDAC channels. J. Biol. Chem. 279, 13575–13583.

    Article  CAS  PubMed  Google Scholar 

  39. Vander Heiden M.G., Li X.X., Gottleib E., Hill R.B., Thompson C.B., 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  CAS  PubMed  Google Scholar 

  40. Vander Heiden M.G., Chandel N.S., Li X.X., Schumacker P.T., Colombini M., Thompson C.B. 2000. Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc. Natl. Acad. Sci. U. S. A. 97, 4666–4671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tikunov A., Johnson C.B., Pediaditakis P., Markevich N., Macdonald J.M., Lemasters J.J., Holmuhamedov E. 2010. Closure of VDAC causes oxidative stress and accelerates the Ca2+-induced mitochondrial permeability transition in rat liver mitochondria. Arch. Biochem. Biophys. 495, 174–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tan W. 2012. VDAC blockage by phosphorothioate oligonucleotides and its implication in apoptosis. Biochim. Biophys. Acta-Biomembr. 1818, 1555–1561.

    Article  CAS  Google Scholar 

  43. Tan W., Colombini M. 2007. VDAC closure increases calcium ion flux. Biochim. Biophys. Acta. 1768, 2510–2515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shoshan-Barmatz V., Ben-Hail D., Admoni L., Krelin Y., Tripathi S.S. 2014. The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim. Biophys. Acta?Biomembr. 1848 (10), 2547–2575. doi 10.1016/jbbamem.2014.10.040

    Article  CAS  Google Scholar 

  45. Keinan N., Pahima H., Ben-Hail D., Shoshan-Barmatz V. 2013. The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis. Biochim. Biophys. Acta-Mol. Cell Res. 1833, 1745–1754.

    Article  CAS  Google Scholar 

  46. Vander Heiden M.G., Li X.X., Gottleib E., Hill R.B., Thompson C.B., 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  CAS  PubMed  Google Scholar 

  47. Chiara F., Castellaro D., Marin O., Petronilli V., Brusilow W.S., Juhaszova M., Sollott S.J., Forte M., Bernardi P., Rasola A. 2008. Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltagedependent anion channels. PLoS ONE. 3, e1852.

    Article  CAS  Google Scholar 

  48. Azoulay-Zohar H., Israelson A., Abu-Hamad S., Shoshan-Barmatz V. 2004. In self-defence: Hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem. J. 377, 347–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gottlob K., Majewski N., Kennedy S., Kandel E., Robey R.B., Hay N. 2001. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Miyamoto S., Murphy A.-N., Brown J.H. 2008. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase- II. Cell Death Differ. 15, 521–529.

    Article  CAS  PubMed  Google Scholar 

  51. Robey R.B., Hay N. 2006. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 25, 4683–4696.

    Article  CAS  PubMed  Google Scholar 

  52. Majewski N., Nogueira V., Robey R.B., Hay N. 2004. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol. Cell. Biol. 24, 730–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zaid H., Abu-Hamad S., Israelson A., Nathan I., Shoshan-Barmatz V. 2005. The voltage-dependent anion channel-1 modulates apoptotic cell death. Cell Death Differ. 12, 751–760.

    Article  CAS  PubMed  Google Scholar 

  54. Cesura A.M., Pinard E., Schubenel R., Goetschy V., Friedlein A., Langen H., Polcic P., Forte M.-A., Bernardi P., Kemp J.-A. 2003. The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore. J. Biol. Chem. 278, 49812–49818.

    Article  CAS  PubMed  Google Scholar 

  55. Zheng Y., Shi Y., Tian C., Jiang C., Jin H., Chen J., Almasan A., Tang H., Chen Q. 2004. Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene. 23, 1239–1247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Krauskopf A., Eriksson O., Craigen W.J., Forte M.-A., Bernardi P. 2006. Properties of the permeability transition in VDAC1–/–mitochondria. Biochim. Biophys. Acta. 1757, 590–595.

    Article  CAS  PubMed  Google Scholar 

  57. Baines C.P., Kaiser R. a, Sheiko T., Craigen W.J., Molkentin J.D. 2007. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat. Cell Biol. 9, 550–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McCommis K.S., Baines C.P. 2012. The role of VDAC in cell death: Friend or foe? Biochim. Biophys. Acta. 1818, 1444–1450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Halestrap A.P., Brenner C. 2003. The adenine nucleotide translocase: A central component of the mitochondrial permeability transition pore and key player in cell death. Curr. Med. Chem. 10, 1507–1525.

    Article  CAS  PubMed  Google Scholar 

  60. Hoffmann B., Stöckl A., Schlame M., Beyer K., Klingenberg M. 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  PubMed  Google Scholar 

  61. Brustovetsky N., Klingenberg M. 1996. Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. Biochemistry. 35, 8483–8488.

    Article  CAS  PubMed  Google Scholar 

  62. Klingenberg M. 2008. The ADP and ATP transport in mitochondria and its carrier. Biochim. Biophys. Acta. 1778, 1978–2021.

    Article  CAS  PubMed  Google Scholar 

  63. McStay G.P., Clarke S.J., Halestrap A.P. 2002. Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem. J. 367, 541–548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bauer M.K.A. 1999. Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J. Cell Biol. 147, 1493–1502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zamora M., Granell M., Mampel T., Viñas O. 2004. Adenine nucleotide translocase 3 (ANT3) overexpression induces apoptosis in cultured cells. FEBS Lett. 563, 155–160.

    Article  CAS  PubMed  Google Scholar 

  66. Schubert A., Grimm S. 2004. Cyclophilin D, a component of the permeability transition-pore, is an apoptosis repressor. Cancer Res. 64 (1), 85–93.

    Article  CAS  PubMed  Google Scholar 

  67. Chevrollier A., Loiseau D., Chabi B., Renier G., Douay O., Malthiè ry Y., Stepien G. 2005. ANT2 isoform required for cancer cell glycolysis. J. Bioenerg. Biomembr. 37, 307–316.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Belzacq A., Vieira H.L.A., Verrier F., Cohen I., Larquet E., Pariselli F., Petit P.X., Kahn A., Rizzuto R., Brenner C., Kroemer G. 2003. Bcl-2 and Bax modulate adenine nucleotide translocase activity. Cancer Res. 63, 541–546.

    CAS  PubMed  Google Scholar 

  70. Marzo I., Brenner C., Zamzami N., Susin S.-A., Beutner G., Brdiczka D., Rémy R., Xie Z.H., Reed J.C., Kroemer G. 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  PubMed  PubMed Central  Google Scholar 

  71. Marzo I., Brenner C., Zamzami N., Jurgensmeier J.M., Susin S.-A., Vieira H.L.A., Prevost Z.X., Matsuyama S., Reed J.C., Kroemer G. 1998. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science. 281, 2027–2031.

    Article  CAS  PubMed  Google Scholar 

  72. Jacotot E., Ferri K.F., El Hamel C., Brenner C., Druillennec S., Hoebeke J., Rustin P., Métivier D., Lenoir C., Geuskens M., Vieira H.L., Loeffler M., Belzacq A.-S., Briand J.P., Zamzami N., et al. 2001. Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2. J. Exp. Med. 193, 509–519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kokoszka J.E., Waymire K.G., Levy S.E., Sligh J.E., Cai J., Jones dean P., MacGregor G.R., Wallace D.C. 2004. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature. 427, 461–465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dolce V., Scarcia P., Iacopetta D., Palmieri F. 2005. A fourth ADP/ATP carrier isoform in man: Identification, bacterial expression, functional characterization and tissue distribution. FEBS Lett. 579, 633–637.

    Article  CAS  PubMed  Google Scholar 

  75. Brower J.V., Rodic N., Seki T., Jorgensen M., Fliess N., Yachnis A.T., McCarrey J.R., Oh S.P., Terada N. 2007. Evolutionarily conserved mammalian adenine nucleotide translocase 4 is essential for spermatogenesis. J. Biol. Chem. 282, 29658–29666.

    Article  CAS  PubMed  Google Scholar 

  76. Hayes J.D., Pulford D.J. 1995. The glutathione Stransferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 30, 445–600.

    Article  CAS  PubMed  Google Scholar 

  77. Verrier F., Deniaud A., Lebras M., Mé tivier D., Kroemer G., Mignotte B., Jan G., Brenner C. 2004. Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis. Oncogene. 23, 8049–8064.

    Article  CAS  PubMed  Google Scholar 

  78. Crompton M., Virji S., Ward J.M. 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  CAS  PubMed  Google Scholar 

  79. Halestrap A.P., Davidson A.M. 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 its interacting with the adenine nucleotide. Biochem. J. 268, 153–160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nicolli A., Basso E., Petronilli V., Wenger R.M., Bernardi P. 1996. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, a cyclosporin A-sensitive channel. J. Biol. Chem. 271, 2185–2192.

    Article  CAS  PubMed  Google Scholar 

  81. Javadov S., Karmazyn M., Escobales N. 2009. Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. Persp. Pharmacol. 330, 670–678.

    CAS  Google Scholar 

  82. Soriano M.E., Nicolosi L., Bernardi P. 2004. Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factoralpha. J. Biol. Chem. 279, 36803–36808.

    Article  CAS  PubMed  Google Scholar 

  83. Nakagawa T., Shimizu S., Watanabe T. 2005. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 434, 652–658.

    Article  CAS  PubMed  Google Scholar 

  84. Baines C.P., Kaiser R.A., Purcell N.H., Blair S.N., Osinka H., Hambleton M.A., Brunskill E.W., Sayen R.M., Gottlieb R.A., Dorn G.W., Robbins J., Molkentin J.D. 2005. Loss of cyclophilin D reveals a critical role for mitochodrial permeability transition in cell death. Nature. 434, 658–662.

    Article  CAS  PubMed  Google Scholar 

  85. Basso E., Fante L., Fowlkes J., Petronilli V., Forte M.-A., Bernardi P. 2005. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J. Biol. Chem. 280, 18558–18561.

    Article  CAS  PubMed  Google Scholar 

  86. Schinzel A.C., Takeuchi O., Huang Z., Fisher J.K., Zhou Z., Rubens J., Hetz C., Danial N.N., Moskowitz M.-A., Korsmeyer S.J. 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  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang X., Carlsson Y., Basso E., Zhu C., Rousset C.I., Rasola A., Johansson B.R., Blomgren K., Mallard C., Bernardi P., Forte M.-A., Hagberg H. 2009. Developmental shift of cyclophilin D contribution to hypoxicischemic brain injury. J. Neurosci. 29, 2588–2596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Forte M., Gold B.G., Marracci G., Chaudhary P., Basso E., Johnsen D., Yu X., Fowlkes J., Rahder M., Stem K., Bernardi P., Bourdette D. 2007. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 104, 7558–7563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Du H., Guo L., Fang F., Chen D., Sosunov A.A., McKhann G.M., Yan Y., Wang C., Zhang H., Molkentin J.D., Gunn-Moore F.J., Vonsattel J.P., Arancio O., Chen J.X., Yan S. Du. 2008. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat. Med. 14, 1097–1105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Elrod J.W., Wong R., Mishra S., Vagnozzi R.J., Sakthievel B., Goonasekera S.A., Karch J., Gabel S., Farber J., Force T., Brown J.H., Murphy E., Molkentin J.D. 2010. Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice. J. Clin. Invest. 120, 3680–3687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Argaud L., Gateau-Roesch O., Muntean D., Chalabreysse L., Loufouat J., Robert D., Ovize M. 2005. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J. Mol. Cell. Cardiol. 38, 367–374.

    Article  CAS  PubMed  Google Scholar 

  92. Nathan M., Friehs I., Choi Y.-H., Cowan D.B., Cao-Danh H., McGowan F.X., del Nido P.J. 2005. Cyclophilin D but not FK-506 protects against dopamineinduced apoptosis in the stunned heart. Ann. Torac. Surg. 79, 1620–1626.

    Article  Google Scholar 

  93. Shchepina L.-A., Pletjushkina O.Y., Avetisyan A.V, Bakeeva L.E., Fetisova E.K., Izyumov D.S., Saprunova V.B., Vyssokikh M.Y., Chernyak B.V, Skulachev V.P. 2002. Oligomycin, inhibitor of the F0 part of H+-ATP-synthase, suppresses the TNF-induced apoptosis. Oncogene. 21, 8149–8157.

    Article  CAS  PubMed  Google Scholar 

  94. Sairanen T., Karjalainen-Lindsberg M.-L., Paetau A., Ijäs P., Lindsberg P.J. 2006. Apoptosis dominant in the periinfarct area of human ischaemic stroke: A possible target of antiapoptotic treatments. Brain: J. Neurol. 129, 189–199.

    Article  Google Scholar 

  95. Kerr P.M., Suleiman M.S., Halestrap A.P. 1999. Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am. J. Physiol. 276, H496–H502.

    CAS  PubMed  Google Scholar 

  96. Halestrap A.P., Doran E., Gillespie J.P., Toole A.O. 2000. Mitochondria and cell death. Biochem. Soc. Trans. 28 (2), 70–77.

    Article  Google Scholar 

  97. Mullauer F.B., Kessler J.H., Medema J.P. 2009. Betulinic acid induces cytochrome c release and apoptosis in a Bax/Bak-independent, permeability transition pore dependent fashion. Apoptosis. 14, 191–202.

    Article  CAS  PubMed  Google Scholar 

  98. Raymond M.-A., Mollica L., Vigneault N., Chan J.S.D., Filep J.G., He E. 2003. Blockade of the apoptotic machinery by Cyclophilin D redirects cell death toward necrosis in arterial endothelial cells?: regulation by reactive oxygen species and cathepsin D1. FASEB J. 17, 515–517.

    CAS  PubMed  Google Scholar 

  99. Cassarino D.S., Swerdlow R.H., Parks J.K., Parker W.D., Bennett J.P. 1998. Cyclophilin D increases resting mitochondrial membrane potential in SY5Y cells and reverses the depressed mitochondrial membrane potential of Alzheimer’s disease cybrids. Biochem. Biophys. Res. Commun. 248, 168–173.

    Article  CAS  PubMed  Google Scholar 

  100. Kruman I.I., Mattson M.P. 1999. Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J. Neurochem. 72, 529–540.

    Article  CAS  PubMed  Google Scholar 

  101. Lin D.-T., Lechleiter J.D. 2002. Mitochondrial targeted Cyclophilin D protects cells from cell death by peptidyl prolyl isomerization. J. Biol. Chem. 277, 31134–31141.

    Article  CAS  PubMed  Google Scholar 

  102. Li Y., Johnson N., Capano M., Edwards M., Crompton M. 2004. Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem. J. 383, 101–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Machida K., Ohta Y., Osada H. 2006. Suppression of apoptosis by Cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells. J. Biol. Chem. 281, 14314–14320.

    Article  CAS  PubMed  Google Scholar 

  104. Li M., Wang H., Li F., Fisher W.E., Chen C., Yao Q. 2005. Effect of cyclophilin A on gene expression in human pancreatic cancer cells. Am. J. Surg. 190, 739–745.

    Article  CAS  PubMed  Google Scholar 

  105. Shen J., Person M.D., Zhu J., Abbruzzese J.L., Li D. 2004. Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by twodimensional gel electrophoresis and mass spectrometry protein expression profiles in pancreatic adenocar. Cancer Res. 64, 9018–9026.

    Article  CAS  PubMed  Google Scholar 

  106. Choi K.J., Piao Y.J., Lim M.J., Kim J.H., Ha J., Choe W., Kim S.S. 2007. Overexpressed cyclophilin A in cancer cells renders resistance to hypoxia- and cisplatin- induced cell death. Cancer Res. 67, 3654–3662.

    Article  CAS  PubMed  Google Scholar 

  107. Howard B.-A., Furumai R., Campa M.J., Rabbani Z.N., Vujaskovic Z., Wang X.-F., Patz E.F. 2005. Stable RNA interference-mediated suppression of cyclophilin A diminishes non-small-cell lung tumor growth in vivo. Cancer Res. 65, 8853–8860.

    Article  CAS  PubMed  Google Scholar 

  108. Yang H., Chen J., Yang J., Qiao S., Zhao S., Yu L. 2007. Cyclophilin A is upregulated in small cell lung cancer and activates ERK1/2 signal. Biochem. Biophys. Res. Commun. 361, 763–767.

    Article  CAS  PubMed  Google Scholar 

  109. Han X., Yoon S.H., Ding Y., Choi T.G., Choi W.J., Kim Y.H., Kim Y., Huh Y., Ha J., Kim S.S. 2010. Cyclophilin D and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells. Oncology Repts. 23, 1053–1062.

    CAS  Google Scholar 

  110. Lee J. 2010. Novel combinational treatment of cisplatin with cyclophilin A inhibitors in human heptocellular carcinomas. Arch. Pharm. Res. 33, 1401–1409.

    Article  CAS  PubMed  Google Scholar 

  111. Bonfils C., Bec N., Larroque C., Del Rio M., Gongora C., Pugnière M., Martineau P. 2010. Cyclophilin A as negative regulator of apoptosis by sequestering cytochrome c. Biochem. Biophys. Res. Commun. 393, 325–330.

    Article  CAS  PubMed  Google Scholar 

  112. Eliseev R., Malecki J., Lester T., Zhang Y., Humphrey J., Gunter T. 2009. Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect. J. Biol. Chem. 284, 9692–9699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shulga N., Wilson-Smith R., Pastorino J.G. 2010. Sirtuin- 3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria. J. Cell Sci. 123, 894–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pellegrini L., Pucci B., Villanova L., Marino M.L., Marfe G., Sansone L., Vernucci E., Bellizzi D., Reali V., Fini M., Russo M.-A., Tafani M. 2012. SIRT3 protects from hypoxia and staurosporinemediated cell death by maintaining mitochondrial membrane potential and intracellular pH. Cell Death Differ. 19, 1815–1825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hafner A.V, Dai J., Gomes A.P., Xiao C.-Y., Palmeira C.M., Rosenzweig A., Sinclair D.-A. 2010. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging. 2, 914–923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Vaseva A., Moll U.M. 2009. The mitochondrial p53 pathway. Biochim. Biophys. Acta. 1787, 1–13.

    Article  CAS  Google Scholar 

  117. Marchenko N.D. 2000. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem. 275, 16202–16212.

    CAS  PubMed  Google Scholar 

  118. Mihara M., Erster S., Zaika A., Petrenko O., Chittenden T., Pancoska P., Moll U.M. 2003. P53 Has a direct apoptogenic role at the mitochondria. Mol. Cell. 11, 577–590.

    Article  CAS  PubMed  Google Scholar 

  119. Marchenko N.D., Wolff S., Erster S., Becker K., Moll U.M. 2007. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J. 26, 923–934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Vaseva A.V., Marchenko N.D., Ji K., Tsirka S.E.T., Holzmann S., Moll U.M. 2012. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell. 149, 1536–1548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhao L.-P., Ji C., Lu P.-H., Li C., Xu B., Gao H. 2013. Oxygen glucose deprivation (OGD)/re-oxygenationinduced in vitro neuronal cell death involves mitochondrial cyclophilin-D/P53 signaling axis. Neurochem. Res. 38, 705–713.

    Article  CAS  PubMed  Google Scholar 

  122. Chen B., Xu M., Zhang H., Wang J.-X., Zheng P., Gong L., Wu G.-J., Dai T. 2013. Cisplatin-induced non-apoptotic death of pancreatic cancer cells requires mitochondrial cyclophilin-D-p53 signaling. Biochem. Biophys. Res. Commun. 437 (4), 526–531. doi 10.1016/jbbrc.2013.06.103

    Article  CAS  PubMed  Google Scholar 

  123. Lu J.-H., Shi Z.-F., Xu H. 2013. The mitochondrial cyclophilin D/p53 complexation mediates doxorubicin- induced non-apoptotic death of A549 lung cancer cells. Mol. Cell. Biochem. 389 (1–2), 17–24. doi 10.1007/s11010-013-1922-110.1007/s11010-013-1922-1

    PubMed  Google Scholar 

  124. Zhang L.-Y., Wu Y.-L., Gao X.-H., Guo F. 2014. Mitochondrial protein cyclophilin-D-mediated programmed necrosis attributes to berberine-induced cytotoxicity in cultured prostate cancer cells. Biochem. Biophys. Res. Commun. 450, 697–703.

    Article  CAS  PubMed  Google Scholar 

  125. Rodriguez-Enriquez S., He L., Lemasters J.J. 2004. Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int. J. Biochem. Cell Biol. 36, 2463–2472.

    Article  CAS  PubMed  Google Scholar 

  126. Lin C.-J., Lee C.-C., Shih Y.-L., Lin C.-H., Wang S.-H., Chen T.-H., Shih C.-M. 2012. Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomide-induced apoptosis in glioma cells. PLoS ONE. 7, e38706.

    Article  CAS  Google Scholar 

  127. Rickmann M., Vaquero E.C., Malagelada J.R., Molero X. 2007. Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway. Gastroenterology. 132, 2518–2532.

    Article  CAS  PubMed  Google Scholar 

  128. Sy L.-K., Yan S.-C., Lok C.-N., Man R.Y.K., Che C.-M. 2008. Timosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells. Cancer Res. 68, 10229–10237.

    Article  CAS  PubMed  Google Scholar 

  129. Yang Y., Xing D., Zhou F., Chen Q. 2010. Mitochondrial autophagy protects against heat shock-induced apoptosis through reducing cytosolic cytochrome c release and downstream caspase-3 activation. Biochem. Biophys. Res. Commun. 395, 190–195.

    Article  CAS  PubMed  Google Scholar 

  130. Elmore S.P., Qian T., Grissom S.F., Lemasters J.J. 2001. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 15, 2286–2287.

    CAS  PubMed  Google Scholar 

  131. Leung A.W.C., Varanyuwatana P., Halestrap A.P. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Alcalá S., Klee M., Fernández J., Fleischer a, Pimentel- Muiños F.X. 2008. A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release. Oncogene. 27, 44–54.

    Article  PubMed  CAS  Google Scholar 

  133. Varanyuwatana P., Halestrap A.P. 2012. The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. Mitochondrion. 12, 120–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chinopoulos C., Konràd C., Kiss G., Metelkin E., Torocsik B., Zhang S.F., Starkov A.A. 2011. Modulation of F0 F1-ATP synthase activity by Cyclophilin D regulates matrix adenine nucleotide levels. FEBS J. 278, 1112–1125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Morciano G., Giorgi C., Bonora M., Punzetti S., Pavasini R., Wieckowski M.R., Campo G., Pinton P. 2015. Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. J. Mol. Cell. Cardiol. 78C, 142–153.

    Article  CAS  Google Scholar 

  136. Bonora M., Wieckowski M.R., 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 (12), 1475–1486.

    Article  PubMed  CAS  Google Scholar 

  137. Giorgio V., von Stockum S., Antoniel M., Fabbro A., Fogolari F., Forte M., Glick G.D., Petronilli V., Zoratti M., Szabó… I., Lippe G., Bernardi P. 2013. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Natl. Acad. Sci. U. S. A. 110, 5887–5892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Giorgio V., Bisetto E., Soriano M.E., Dabbeni-Sala F., Basso E., Petronilli V., Forte M.-A., 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  CAS  PubMed  PubMed Central  Google Scholar 

  139. Acín-Pérez R., Fernández-Silva P., Peleato M.L., Pérez-Martos A., Enriquez J.A. 2008. Respiratory active mitochondrial supercomplexes. Mol. Cell. 32, 529–539.

    Article  PubMed  CAS  Google Scholar 

  140. Wittig I., Schägger H. 2008. Structural organization of mitochondrial ATP synthase. Biochim. Biophys. Acta. 1777, 592–598.

    Article  CAS  PubMed  Google Scholar 

  141. Chen C., Ko Y., Delannoy M., Ludtke S.J., Chiu W., Pedersen P.L. 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  CAS  PubMed  Google Scholar 

  142. Alavian K.N., Li H., Collis L., Bonanni L., Zeng L., Sacchetti S., Lazrove E., Nabili P., Flaherty B., Graham M., Chen Y., Messerli S., Mariggio M.A., Rahner C., Mcnay E., Shore G., Smith P.J.S., Hardwick J.M., Jonas E.A. 2012. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat. Cell Biol. 13, 1224–1233.

    Article  CAS  Google Scholar 

  143. Perciavalle R.M., Stewart D.P., Koss B., Lynch J., Milasta S., Bathina M., Temirov J., Cleland M.M., Pelletier S., Schuetz J.D., Youle R.J., Green D.R., Opferman J.T. 2012. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat. Cell Biol. 14, 575–583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen Y.-B., Aon M.A., Hsu Y.-T., Soane L., Teng X., McCaffery J.M., Cheng W.-C., Qi B., Li H., Alavian K.N., Dayhoff-Brannigan M., Zou S., Pineda F.J., O’Rourke B., Ko Y.H., et al. 2011. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J. Cell Biol. 195, 263–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Alavian K.N., Beutner G., Lazrove E., Sacchetti S., Park H.-A., Licznerski P., Li H., Nabili P., Hockensmith K., Graham M., Porter G.-A., Jonas E.-A. 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  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zoratti M., De Marchi U., Biasutto L., Szabò I. 2010. Electrophysiology clarifies the megariddles of the mitochondrial permeability transition pore. FEBS Lett. 584, 1997–2004.

    Article  CAS  PubMed  Google Scholar 

  147. Meinecke M., Wagner R., Kovermann P., Guiard B., Mick D.U., Hutu D.P., Voos W., Truscott K.N., Chacinska A., Pfanner N., Rehling P. 2006. Tim50 maintains the permeability barrier of the mitochondrial inner membrane. Science. 312, 1523–1526.

    Article  CAS  PubMed  Google Scholar 

  148. Guo Y., Cheong N., Zhang Z., De Rose R., Deng Y., Farber S.A., Fernandes-Alnemri T., Alnemri E.S. 2004. Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death. J. Biol. Chem. 279, 24813–24825.

    Article  CAS  PubMed  Google Scholar 

  149. Saddar S., Dienhart M.K., Stuart R.A. 2008. The F1F0-ATP synthase complex influences the assembly state of the cytochrome bc1-cytochrome oxidase supercomplex and its association with the TIM23 machinery. J. Biol. Chem. 283, 6677–6686.

    Article  CAS  PubMed  Google Scholar 

  150. Kwong J.Q., Molkentin J.D. 2015. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab. 21, 206–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Griffiths E.J., Halestrap A.P. 1993. Protection by Cyclophilin D of ischemia/reperfusion-induced damage in isolated rat hearts. J. Mol. Cell. Cardiol. 25, 1461–1469.

    Article  CAS  PubMed  Google Scholar 

  152. Friberg H., Ferrand-Drake M., Bengtsson F., Halestrap A.-P., Wieloch T. 1998. Cyclophilin D, but not FK506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death. J. Neurosci. 18, 5151–5159.

    CAS  PubMed  Google Scholar 

  153. Li P.A., Uchino H., Elmér E., Siesjö B.K. 1997. Amelioration by Cyclophilin D of brain damage following 5 or 10 min of ischemia in rats subjected to preischemic hyperglycemia. Brain Res. 753, 133–140.

    Article  CAS  PubMed  Google Scholar 

  154. Irwin W.A., Bergamin N., Sabatelli P., Reggiani C., Megighian A., Merlini L., Braghetta P., Columbaro M., Volpin D., Bressan G.M., Bernardi P., Bonaldo P. 2003. collagen VIdeficiency. Nat. Genet. 35, 367–371.

  155. Keep M., Elmér E., Fong K.S., Csiszar K. 2001. Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res. 894, 327–331.

    Article  CAS  PubMed  Google Scholar 

  156. Haouzi D., Cohen I., Vieira H.L.A., Poncet D., Boya P., Castedo M., Vadrot N., Belzacq A.-S., Fau D., Brenner C., Feldmann G., Kroemer G. 2002. Mitochondrial permeability transition as a novel principle of hepatorenal toxicity in vivo. Apoptosis. 7, 395–405.

    Article  CAS  PubMed  Google Scholar 

  157. Soriano M.E., Nicolosi L., Bernardi P. 2004. Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor- alpha. J. Biol. Chem. 279, 36803–36808.

    Article  CAS  PubMed  Google Scholar 

  158. Klöhn P.-C., Soriano M.E., Irwin W., Penzo D., Scorrano L., Bitsch A., Neumann H.-G., Bernardi P. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Griffiths E.J., Halestrap A.-P. 1995. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem. J. 307, 93–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Di Lisa F., Menabò R., Canton M., Barile M., Bernardi P. 2001. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J. Biol. Chem. 276, 2571–2575.

    Article  PubMed  Google Scholar 

  161. Xu D., Bureau Y., McIntyre D.C., Nicholson D.W., Liston P., Zhu Y., Fong W.G., Crocker S.J., Korneluk R.G., Robertson G.S. 1999. Attenuation of ischemia- induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus. J. Neurosci. 19, 5026–5033.

    CAS  PubMed  Google Scholar 

  162. Bott-Flügel L., Weig H.-J., Knödler M., Städele C., Moretti A., Laugwitz K.-L., Seyfarth M. 2005. Gene transfer of the pancaspase inhibitor P35 reduces myocardial infarct size and improves cardiac function. J. Mol. Med. 83, 526–534.

    Article  PubMed  CAS  Google Scholar 

  163. Degterev A., Huang Z., Boyce M., Li Y., Jagtap P., Mizushima N., Cuny G.D., Mitchison T.J., Moskowitz M.A., Yuan J. 2005. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119.

    Article  CAS  PubMed  Google Scholar 

  164. Watanabe T., Otsu K., Takeda T., Yamaguchi O., Hikoso S., Kashiwase K., Higuchi Y., Taniike M., Nakai A., Matsumura Y., Nishida K., Ichijo H., Hori M. 2005. Apoptosis signal-regulating kinase 1 is involved not only in apoptosis but also in non-apoptotic cardiomyocyte death. Biochem. Biophys. Res. Commun. 333, 562–567.

    Article  CAS  PubMed  Google Scholar 

  165. Bernardi P., Krauskopf A., Basso E., Petronilli V., Blachly-Dyson E., Blalchy-Dyson E., Di Lisa F., Forte M.-A. 2006. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. 273, 2077–2099.

    Article  CAS  PubMed  Google Scholar 

  166. Rao V.K., Carlson E.A., Yan S.S. 2014. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim. Biophys. Acta. 1842, 1267–1272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Guo L., Du H., Yan S., Wu X., McKhann G.M., Chen J.X., Yan S.S. 2013. Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer’s neurons. PLoS ONE. 8 (1), e54914.

    Article  CAS  Google Scholar 

  168. Hashimoto M., Rockenstein E., Crews L., Masliah E. 2003. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromol. Med. 4, 21–36.

    Article  CAS  Google Scholar 

  169. Shen J., Du T., Wang X., Duan C., Gao G., Zhang J., Lu L., Yang H. 2014. a-Synuclein amino terminus regulates mitochondrial membrane permeability. Brain Res. 1591, 14–26.

    Article  CAS  PubMed  Google Scholar 

  170. Shinohara Y., Ishida T., Hino M., Yamazaki N., Baba Y., Terada H. 2000. Characterization of porin isoforms expressed in tumor cells. Eur. J. Bochem. 267, 6067–6073.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Basic Medicine, M.V. Lomonosov Moscow State University, 119991, Moscow, Russia

    E. A. Novoderezhkina, B. D. Zhivotovsky & V. G. Gogvadze

  2. Division of Toxicology, Karolinska Institutet, Institute of Environmental Medicine, Stockholm, 17177, Sweden

    B. D. Zhivotovsky & V. G. Gogvadze

Authors
  1. E. A. Novoderezhkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. D. Zhivotovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. G. Gogvadze
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. G. Gogvadze.

Additional information

Original Russian Text © E.A. Novoderezhkina, B.D. Zhivotovsky, V.G. Gogvadze, 2016, published in Molekulyarnaya Biologiya, 2016, Vol. 50, No. 1, pp. 51–68.

The article was translated by the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Novoderezhkina, E.A., Zhivotovsky, B.D. & Gogvadze, V.G. Induction of unspecific permeabilization of mitochondrial membrane and its role in cell death. Mol Biol 50, 43–58 (2016). https://doi.org/10.1134/S0026893316010167

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893316010167

Keywords

Search

Navigation