VDAC regulation: role of cytosolic proteins and mitochondrial lipids



It was recently asserted that the voltage-dependent anion channel (VDAC) serves as a global regulator, or governor, of mitochondrial function (Lemasters and Holmuhamedov, Biochim Biophys Acta 1762:181–190, 2006). Indeed, VDAC, positioned on the interface between mitochondria and the cytosol (Colombini, Mol Cell Biochem 256:107–115, 2004), is at the control point of mitochondria life and death. This large channel plays the role of a “switch” that defines in which direction mitochondria will go: to normal respiration or to suppression of mitochondria metabolism that leads to apoptosis and cell death. As the most abundant protein in the mitochondrial outer membrane (MOM), VDAC is known to be responsible for ATP/ADP exchange and for the fluxes of other metabolites across MOM. It controls them by switching between the open and “closed” states that are virtually impermeable to ATP and ADP. This control has dual importance: in maintaining normal mitochondria respiration and in triggering apoptosis when cytochrome c and other apoptogenic factors are released from the intermembrane space into the cytosol. Emerging evidence indicates that VDAC closure promotes apoptotic signals without direct involvement of VDAC in the permeability transition pore or hypothetical Bax-containing cytochrome c permeable pores. VDAC gating has been studied extensively for the last 30 years on reconstituted VDAC channels. In this review we focus exclusively on physiologically relevant regulators of VDAC gating such as endogenous cytosolic proteins and mitochondrial lipids. Closure of VDAC induced by such dissimilar cytosolic proteins as pro-apoptotic tBid and dimeric tubulin is compared to show that the involved mechanisms are rather distinct. While tBid mostly modulates VDAC voltage gating, tubulin blocks the channel with the efficiency of blockage controlled by voltage. We also discuss how characteristic mitochondrial lipids, phospatidylethanolamine and cardiolipin, could regulate VDAC gating. Overall, we demonstrate that VDAC gating is not just an observation made under artificial conditions of channel reconstitution but is a major mechanism of MOM permeability control.


Apoptosis Mitochondria Mitochondria outer membrane Voltage dependent anion channel VDAC Channel gating Tubulin tBid Cardiolipin Lipid packing stress 


  1. Andre N, Carre M, Brasseur G, Pourroy B, Kovacic H, Briand C, Braguer D (2002) FEBS Lett 532:256–260CrossRefGoogle Scholar
  2. Appaix F, Kuznetsov AV, Usson Y, Kay L, Andrienko T, Olivares J, Kaambre T, Sikk P, Margreiter R, Saks V (2003) Exp Physiol 88:175–190CrossRefGoogle Scholar
  3. Ardail D, Privat JP, Egretcharlier M, Levrat C, Lerme F, Louisot P (1990) J Biol Chem 265:18797–18802Google Scholar
  4. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) Biochem J 377:347–355CrossRefGoogle Scholar
  5. Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Nat Cell Biol 9:550–555CrossRefGoogle Scholar
  6. Basanez G, Sharpe JC, Galanis J, Brandt TB, Hardwick JM, Zimmerberg J (2002) J Biol Chem 277:49360–49365CrossRefGoogle Scholar
  7. Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F, Forte MA (2006) FEBS J 273:2077–2099CrossRefGoogle Scholar
  8. Bernier-Valentin F, Rousset B (1982) J Biol Chem 257:7092–7099Google Scholar
  9. Beutner G, Ruck A, Riede B, Welte W, Brdiczka D (1996) FEBS Lett 396:189–195CrossRefGoogle Scholar
  10. Bezrukov SM (2000) Curr Opin Colloid Interface Sci 5:237–243CrossRefGoogle Scholar
  11. Bezrukov SM, Rand RP, Vodyanoy I, Parsegian VA (1998) Faraday Discuss 111:173–183CrossRefGoogle Scholar
  12. Brink-van der Laan EV, Killian JA, de Kruijff B (2004) Biochim Biophys Acta 1666:275–288CrossRefGoogle Scholar
  13. Cantor RS (1999) Biophys J 76:2625–2639Google Scholar
  14. Carre M, Andre N, Carles G, Borghi H, Brichese L, Briand C, Braguer D (2002) J Biol Chem 277:33664–33669CrossRefGoogle Scholar
  15. Colombini M (1980) J Membr Biol 53:79–84CrossRefGoogle Scholar
  16. Colombini M (1989) J Membr Biol 111:103–111CrossRefGoogle Scholar
  17. Colombini M (2004) Mol Cell Biochem 256:107–115CrossRefGoogle Scholar
  18. Colombini M, Yeung CL, Tung J, König T (1987) Biochim Biophys Acta 905:279–286CrossRefGoogle Scholar
  19. Colombini M, Blachly-Dyson E, Forte M (1996) In: Narahashi T (ed) Ion channels, vol. 4. Plenum, New York, pp 169–202Google Scholar
  20. Cortese JD, Voglino AL, Hackenbrock CR (1992) Biochim Biophys Acta 1100:189–197CrossRefGoogle Scholar
  21. Crompton M (1999) Biochem J 341:233–249CrossRefGoogle Scholar
  22. Doring C, Colombini M (1985) J Membr Biol 83:81–86CrossRefGoogle Scholar
  23. Epand RF, Martinou JC, Fornallaz-Mulhauser M, Hughes DW, Epand RM (2002) J Biol Chem 277:32632–32639CrossRefGoogle Scholar
  24. Esteve MA, Carre M, Braguer D (2007) Curr Cancer Drug Targets 7:713–729CrossRefGoogle Scholar
  25. Galluzzi L, Kroemer G (2007) Nat Cell Biol 9:487–489CrossRefGoogle Scholar
  26. Goforth RL, Chi AK, Greathouse DV, Providence LL, Koeppe RE, Andersen OS (2003) J Gen Physiol 121:477–493CrossRefGoogle Scholar
  27. Gruner SM (1985) Proc Natl Acad Sci USA 82:3665–3669CrossRefGoogle Scholar
  28. Gullingsrud J, Schulten K (2004) Biophys J 86:3496–3509CrossRefGoogle Scholar
  29. Hodge T, Colombini M (1997) J Membr Biol 157:271–279CrossRefGoogle Scholar
  30. Keller SL, Bezrukov SM, Gruner SM, Tate MW, Vodyanoy I, Parsegian VA (1993) Biophys J 65:23–27Google Scholar
  31. Krasilnikov OV, Sabirov RZ, Ternovsky VI, Merzliak PG, Muratkhodjaev JN (1992) FEMS Microbiol Immunol 105:93–100CrossRefGoogle Scholar
  32. Krauskopf A, Eriksson O, Craigen WJ, Forte MA, Bernardi P (2006) Biochim Biophys Acta 1757:590–595CrossRefGoogle Scholar
  33. Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD (2002) Cell 111:331–342CrossRefGoogle Scholar
  34. Lai JC, Tan WZ, Benimetskaya L, Miller P, Colombini M, Stein CA (2006) Proc Natl Acad Sci USA 103:7494–7499CrossRefGoogle Scholar
  35. Lee AC, Zizi M, Colombini M (1994) J Biol Chemi 269:30974–30980Google Scholar
  36. Lee AC, Xu XF, Colombini M (1996) J Biol Chemi 271:26724–26731CrossRefGoogle Scholar
  37. Lemasters JJ, Holmuhamedov E (2006) Biochim Biophys Acta 1762:181–190Google Scholar
  38. Lemeshko VV (2006) Eur Biophys J 36:57–66CrossRefGoogle Scholar
  39. Li XX, Vander Heiden MG, Thompson CB, Colombini M (2001) Biophysi J 80:239A–239AGoogle Scholar
  40. Lutter M, Fang M, Luo X, Nishijima M, Xie XS, Wang XD (2000) Nat Cell Biol 2:754–756CrossRefGoogle Scholar
  41. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004) Mol Cell 16:819–830CrossRefGoogle Scholar
  42. Mannella CA, Guo XW, Cognon B (1989) FEBS Lett 253:231–234CrossRefGoogle Scholar
  43. Mikhailov V, Mikhailova M, Pulkrabek DJ, Dong Z, Venkatachalam MA, Saikumar P (2001) J Biol Chem 276:18361–18374CrossRefGoogle Scholar
  44. Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M, Thompson CB (1997) Nature 385:353–357CrossRefGoogle Scholar
  45. Monge C, Beraud N, Rostovtseva T, Sackett D, Vendelin M, Saks V (2008) Biophys J 94:1562Google Scholar
  46. Pavlov EV, Priault M, Pietkiewicz D, Cheng EHY, Antonsson B, Manon S, Korsmeyer SJ, Mannella CA, Kinnally KW (2001) J Cell Biol 155:725–731CrossRefGoogle Scholar
  47. Peng S, Blachly-Dyson E, Forte M, Colombini M (1992) Biophys J 62:123–135Google Scholar
  48. Polcic P, Forte M (2003) Biochem J 374:393–402CrossRefGoogle Scholar
  49. Porcelli AM, Ghelli A, Zanna C, Pinton P, Rizzuto R, Rugolo M (2005) Biochem Biophys Res Commun 326:799–804CrossRefGoogle Scholar
  50. Priault M, Chaudhuri B, Clow A, Camougrand N, Manon S (1999) Eur J Biochem 260:684–691CrossRefGoogle Scholar
  51. Robey RB, Hay N (2006) Oncogene 25:4683–4696CrossRefGoogle Scholar
  52. Rostovtseva T, Colombini M (1996) J Biol Chem 271:28006–28008CrossRefGoogle Scholar
  53. Rostovtseva T, Colombini M (1997) Biophys J 72:1954–1962Google Scholar
  54. Rostovtseva TK, Komarov A, Bezrukov SM, Colombini M (2002a) Biophys J 82:193–205Google Scholar
  55. Rostovtseva TK, Komarov A, Bezrukov SM, Colombini M (2002b) J Membr Biol 187:147–156CrossRefGoogle Scholar
  56. Rostovtseva TK, Antonsson B, Suzuki M, Youle RJ, Colombini M, Bezrukov SM (2004) J Biol Chem 279:13575–13583CrossRefGoogle Scholar
  57. Rostovtseva TK, Tan WZ, Colombini M (2005) J Bioenerg Biomembranes 37:129–142CrossRefGoogle Scholar
  58. Rostovtseva TK, Kazemi N, Weinrich M, Bezrukov SM (2006) J Biol Chem 281:37496–37506CrossRefGoogle Scholar
  59. Rostovtseva TK, Sackett DL, Sheldon K, Monge C, Saks V, Bezrukov SM (2008) Biophys J 94:1760CrossRefGoogle Scholar
  60. Saks VA, Kuznetsov AV, Khuchua ZA, Vasilyeva EV, Belikova JO, Kesvatera T, Tiivel T (1995) J Mol Cell Cardiol 27:625–645CrossRefGoogle Scholar
  61. Saks V, Dzeja P, Schlattner U, Vendelin M, Terzic A, Wallimann T (2006) J Physiol-London 571:253–273CrossRefGoogle Scholar
  62. Saks V, Vendelin M, Aliev MK, Kekelidze T, Engelbrecht J (2007) In: Gibson GF, Dienel G (eds) Brain energetics: integration of molecular and cellular processes. Springer, Berlin, pp 815–860Google Scholar
  63. Shimizu S, Narita M, Tsujimoto Y (1999) Nature 399:483–487CrossRefGoogle Scholar
  64. Shimizu S, Ide T, Yanagida T, Tsujimoto Y (2000a) J Biol Chem 275:12321–12325CrossRefGoogle Scholar
  65. Shimizu S, Shinohara Y, Tsujimoto Y (2000b) Oncogene 19:4309–4318CrossRefGoogle Scholar
  66. Simbeni R, Pon L, Zinser E, Paltauf F, Daum G (1991) J Biol Chem 266:10047–10049Google Scholar
  67. Song JM, Midson C, Blachly-Dyson E, Forte M, Colombini M (1998a) Biophys J 74:2926–2944Google Scholar
  68. Song JM, Midson C, Blachly-Dyson E, Forte M, Colombini M (1998b) J Biol Chem 273:24406–24413CrossRefGoogle Scholar
  69. Suchyna TM, Tape SE, Koeppe RE, Andersen OS, Sachs F, Gottlieb PA (2004) Nature 430:235–240CrossRefGoogle Scholar
  70. Tan WZ, Colombini M (2007) Biochim Biophys Acta 1768:2510–2515CrossRefGoogle Scholar
  71. Tan WZ, Lai JC, Miller P, Stein CA, Colombini M (2007a) Am J Physiol Cell Physiol 292:C1388–C1397CrossRefGoogle Scholar
  72. Tan WZ, Loke YH, Stein CA, Miller P, Colombini M (2007b) Biophys J 93:1184–1191CrossRefGoogle Scholar
  73. Thomas L, Blachly-Dyson E, Colombini M, Forte M (1993) Proc Natl Acad Sci USA 90:5446–5449CrossRefGoogle Scholar
  74. Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB (2000) Proc Natl Acad Sci USA 97:4666–4671CrossRefGoogle Scholar
  75. Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M (2001) J Biol Chem 276:19414–19419CrossRefGoogle Scholar
  76. Xu X, Forbes JG, Colombini M (2001) J Membr Biol 180:73–81CrossRefGoogle Scholar
  77. Zimmerberg J, Parsegian VA (1986) Nature 323:36–39CrossRefGoogle Scholar
  78. Zizi M, Thomas L, Blachly-Dyson E, Forte M, Colombini M (1995) J Membr Biol 144:121–129Google Scholar
  79. Zizi M, Byrd C, Boxus R, Colombini M (1998) Biophys J 75:704–713Google Scholar
  80. Zoratti M, Szabo D, De Marchi U (2005) Biochim Biophys Acta 1706:40–52CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Laboratory of Physical and Structural Biology, Program in Physical BiologyNICHD, National Institutes of HealthBethesdaUSA

Personalised recommendations