Journal of Bioenergetics and Biomembranes

, Volume 40, Issue 3, pp 183–191 | Cite as

Uncovering the role of VDAC in the regulation of cell life and death



Proper cell activity requires an efficient exchange of molecules between mitochondria and cytoplasm. Lying in the outer mitochondrial membrane, VDAC assumes a crucial position in the cell, forming the main interface between the mitochondrial and the cellular metabolisms. As such, it has been recognized that VDAC plays a crucial role in regulating the metabolic and energetic functions of mitochondria. Indeed, down-regulation of VDAC1 expression by shRNA leads to a decrease in energy production and cell growth. VDAC has also been recognized as a key protein in mitochondria-mediated apoptosis through its involvement in the release of apoptotic proteins located in the inter-membranal space and as the proposed target of pro- and anti-apoptotic members of the Bcl2-family and of hexokinase. Questions, however, remain as to if and how VDAC mediates the transfer of apoptotic proteins from the inter-membranal space to the cytosol. The diameter of the VDAC pore is only about 2.5–3 nm, insufficient for the passage of a folded protein like cytochrome c. New work, however, suggests that pore formation involves the assembly of homo-oligomers of VDAC or hetero-oligomers composed of VDAC and pro-apoptotic proteins, such as Bax. Thus, VDAC appears to represent a convergence point for a variety of cell survival and cell death signals. This review provides insight into the central role of VDAC in mammalian cell life and death, emphasizing VDAC function in the regulation of mitochondria-mediated apoptosis and, as such, its potential as a rational target for new therapeutics.


Apoptosis Cancer Cytochrome c Hexokinase Mitochondria shRNA VDAC 


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  1. Abu-Hamad S, Sivan S, Shoshan-Barmatz V (2006) Proc Natl Acad Sci U S A 103:5787–5792CrossRefGoogle Scholar
  2. Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V (2008) J Biol Chem 283(19):13482–13490CrossRefGoogle Scholar
  3. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) Biochem J 377:347–355CrossRefGoogle Scholar
  4. Bae JH, Park JW, Kwon TK (2003) Biochem Biophys Res Commun 303:1073–1079CrossRefGoogle Scholar
  5. Baek JH, Lee YS, Kang CM, Kim JA, Kwon KS, Son HC, Kim KW (1997) Int J Cancer 73:725–728CrossRefGoogle Scholar
  6. Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Nat Cell Biol 9:550–555CrossRefGoogle Scholar
  7. Banerjee J, Ghosh S (2004) Biochem Biophys Res Commun 323:310–314CrossRefGoogle Scholar
  8. Bathori G, Sahin-Toth M, Fonyo A, Ligeti E (1993) Biochim Biophys Acta 1145:168–176CrossRefGoogle Scholar
  9. Bathori G, Csordas G, Garcia-Perez C, Davies E, Hajnoczky G (2006) J Biol Chem 281:17347–17358CrossRefGoogle Scholar
  10. Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB (2002) J Biol Chem 277:11392–11400CrossRefGoogle Scholar
  11. Colombini M (2004) Mol Cell Biochem 256–257:107–115CrossRefGoogle Scholar
  12. De Pinto V, Messina A, Accardi R, Aiello R, Guarino F, Tomasello MF, Tommasino M, Tasco G, Casadio R, Benz R, De Giorgi F, Ichas F, Baker M, Lawen A (2003) Ital J Biochem 52:17–24Google Scholar
  13. Deniaud A, Rossi C, Berquand A, Homand J, Campagna S, Knoll W, Brenner C, Chopineau J (2007) Langmuir 23:3898–3905CrossRefGoogle Scholar
  14. Ding WX, Shen HM, Ong CN (2001) Biochem Biophys Res Commun 285:1155–1161CrossRefGoogle Scholar
  15. Doran E, Halestrap AP (2000) Biochem J 348:343–350CrossRefGoogle Scholar
  16. Fanciulli M, Paggi MG, Bruno T, Del Carlo C, Bonetto F, Gentile FP, Floridi A (1994) Oncol Res 6:405–409Google Scholar
  17. Florke H, Thinnes FP, Winkelbach H, Stadtmuller U, Paetzold G, Morys-Wortmann C, Hesse D, Sternbach H, Zimmermann B, Kaufmann-Kolle P (1994) Biol Chem Hoppe-Seyler 375:513–520Google Scholar
  18. Gelb BD, Adams V, Jones SN, Griffin LD, MacGregor GR, McCabe ER (1992) Proc Natl Acad Sci U S A 89:202–206CrossRefGoogle Scholar
  19. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Cancer Res 62:3909–3913Google Scholar
  20. Ghosh T, Pandey N, Maitra A, Brahmachari SK, Pillai B (2007) PLoS ONE 2:e1170CrossRefGoogle Scholar
  21. Gincel D, Shoshan-Barmatz V (2004) J Bioenerg Biomembr 36:179–186CrossRefGoogle Scholar
  22. Gincel D, Silberberg SD, Shoshan-Barmatz V (2000) J Bioenerg Biomembr 32:571–583CrossRefGoogle Scholar
  23. Gincel D, Zaid H, Shoshan-Barmatz V (2001) Biochem J 358:147–155CrossRefGoogle Scholar
  24. Godbole A, Varghese J, Sarin A, Mathew MK (2003) Biochim Biophys Acta 1642:87–96CrossRefGoogle Scholar
  25. Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E (2008) Oncogene (in press)Google Scholar
  26. Goncalves RP, Buzhynskyy N, Prima V, Sturgis JN, Scheuring S (2007) J Mol Biol 369:413–418CrossRefGoogle Scholar
  27. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Genes Dev 15:1406–1418CrossRefGoogle Scholar
  28. Granville DJ, Gottlieb RA (2003) Curr Med Chem 10:1527–1533CrossRefGoogle Scholar
  29. Gunter TE, Buntinas L, Sparagna GC, Gunter KK (1998) Biochim Biophys Acta 1366:5–15CrossRefGoogle Scholar
  30. Halestrap AP, Doran E, Gillespie JP, O’Toole A (2000) Biochem Soc Trans 28:170–177Google Scholar
  31. Halestrap AP, McStay GP, Clarke SJ (2002) Biochimie 84:153–166CrossRefGoogle Scholar
  32. Hoogenboom BW, Suda K, Engel A, Fotiadis D (2007) J Mol Biol 370:246–255CrossRefGoogle Scholar
  33. Israelson A, Arzoine L, Abu-hamad S, Khodorkovsky V, Shoshan-Barmatz V (2005) Chem Biol 12:1169–1178CrossRefGoogle Scholar
  34. Israelson A, Abu-Hamad S, Zaid H, Nahon E, Shoshan-Barmatz V (2007a) Cell Calcium 41:235–244CrossRefGoogle Scholar
  35. Israelson A, Zaid H, Abu-Hamad S, Nahon E, Shoshan-Barmatz V (2007b) Cell Calcium 43:196–204CrossRefGoogle Scholar
  36. Juhaszova M, Wang S, Zorov DB, Bradley Nuss H, Gleichmann M, Mattson MP, Sollott SJ (2008) Ann N Y Acad Sci 1123:197–212CrossRefGoogle Scholar
  37. Kroemer G, Galluzzi L, Brenner C (2007) Physiol Rev 87:99–163CrossRefGoogle Scholar
  38. Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N, Tsujimoto Y (2000) Oncogene 19:4807–4814CrossRefGoogle Scholar
  39. Lee AC, Xu X, Colombini M (1996) J Biol Chem 271:26724–26731CrossRefGoogle Scholar
  40. Lemasters JJ (2007) J Gastroenterol Hepatol 22(Suppl 1):S31–S37CrossRefGoogle Scholar
  41. Lemasters JJ, Holmuhamedov E (2006) Biochim Biophys Acta 1762:181–190Google Scholar
  42. Lu AJ, Dong CW, Du CS, Zhang QY (2007) Fish Shellfish Immunol 23:601–613CrossRefGoogle Scholar
  43. Madesh M, Hajnoczky G (2001) J Cell Biol 155:1003–1015CrossRefGoogle Scholar
  44. Malia TJ, Wagner G (2007) Biochemistry 46:514–525CrossRefGoogle Scholar
  45. Martinou JC, Desagher S, Antonsson B (2000) Nat Cell Biol 2:E41–E43CrossRefGoogle Scholar
  46. Mathupala SP, Ko YH, Pedersen PL (2006) Oncogene 25:4777–4786CrossRefGoogle Scholar
  47. Nakashima RA (1986) Biochemistry 25:1015–1021CrossRefGoogle Scholar
  48. Nichols BJ, Denton RM (1995) Mol Cell Biochem 149–150:203–212CrossRefGoogle Scholar
  49. Pastorino JG, Hoek JB (2003) Curr Med Chem 10:1535–1551CrossRefGoogle Scholar
  50. Pastorino JG, Shulga N, Hoek JB (2002) J Biol Chem 277:7610–7618CrossRefGoogle Scholar
  51. Pastorino JG, Hoek JB, Shulga N (2005) Cancer Res 65:10545–10554CrossRefGoogle Scholar
  52. Pedersen PL (2007) J Bioenerg Biomembr 39:211–222CrossRefGoogle Scholar
  53. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002) Biochim Biophys Acta 1555:14–20CrossRefGoogle Scholar
  54. Robey RB, Hay N (2006) Oncogene 25:4683–4696CrossRefGoogle Scholar
  55. Rostovtseva TK, Komarov A, Bezrukov SM, Colombini M (2002) Biophys J 82:193–205CrossRefGoogle Scholar
  56. Rostovtseva TK, Tan W, Colombini M (2005) J Bioenerg Biomembr 37:129–142CrossRefGoogle Scholar
  57. Shi Y, Jiang C, Chen Q, Tang H (2003) Biochem Biophys Res Commun 303:475–482CrossRefGoogle Scholar
  58. Shimizu S, Narita M, Tsujimoto Y (1999) Nature 399:483–487CrossRefGoogle Scholar
  59. Shimizu S, Shinohara Y, Tsujimoto Y (2000a) Oncogene 19:4309–4318CrossRefGoogle Scholar
  60. Shimizu S, Ide T, Yanagida T, Tsujimoto Y (2000b) J Biol Chem 275:12321–12325CrossRefGoogle Scholar
  61. Shimizu S, Matsuoka Y, Shinohara Y, Yoneda Y, Tsujimoto Y (2001) J Cell Biol 152:237–250CrossRefGoogle Scholar
  62. Shoshan-Barmatz V, Gincel D (2003) Cell Biochem Biophys 39:279–292CrossRefGoogle Scholar
  63. Shoshan-Barmatz V, Israelson A (2005) J Membr Biol 204:57–66CrossRefGoogle Scholar
  64. Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N (2004) Biochim Biophys Acta 1657:105–114CrossRefGoogle Scholar
  65. Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu SS (2006) Curr Pharm Des 12:2249–2270CrossRefGoogle Scholar
  66. Shoshan-Barmatz S, Arbel N, Arzoine L (2008) Cell Sci 4:74–118Google Scholar
  67. Simamura E, Hirai K, Shimada H, Koyama J, Niwa Y, Shimizu S (2006) Cancer Biol Ther 5:1523–1529CrossRefGoogle Scholar
  68. Sui D, Wilson JE (1997) Arch Biochem Biophys 345:111–125CrossRefGoogle Scholar
  69. Sun L, Shukair S, Naik TJ, Moazed F, Ardehali H (2007) Mol Cell Biol 28(3):1007–1017CrossRefGoogle Scholar
  70. Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L, Araujo N, Pinna G, Larochette N, Zamzami N, Modjtahedi N, Harel-Bellan A, Kroemer G (2008) Oncogene (in press)Google Scholar
  71. Tan W, Colombini M (2007) Biochim Biophys Acta 1768(10):2510–2515CrossRefGoogle Scholar
  72. Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, Zamzami N, Jan G, Kroemer G, Brenner C (2007) Oncogene 26:2606–2620CrossRefGoogle Scholar
  73. Tsujimoto Y (2003) J Cell Physiol 195:158–167CrossRefGoogle Scholar
  74. Tsujimoto Y, Shimizu S (2002) Biochimie 84:187–193CrossRefGoogle Scholar
  75. Tsujimoto Y, Shimizu S (2007) Apoptosis 12:835–840CrossRefGoogle Scholar
  76. Vyssokikh MY, Brdiczka D (2003) Acta Biochim Pol 50:389–404Google Scholar
  77. Wilson JE (2003) J Exp Biol 206:2049–2057CrossRefGoogle Scholar
  78. Yehezkel G, Hadad N, Zaid H, Sivan S, Shoshan-Barmatz V (2006) J Biol Chem 281:5938–5946CrossRefGoogle Scholar
  79. Yehezkel G, Abu-Hamad S, Shoshan-Barmatz V (2007) J Cell Physiol 212:551–561CrossRefGoogle Scholar
  80. Yu J, Qian H, Li Y, Wang Y, Zhang X, Liang X, Fu M, Lin C (2007) Cancer Biol Ther 6:580–586CrossRefGoogle Scholar
  81. Yuan S, Fu Y, Wang X, Shi H, Huang Y, Song X, Li L, Song N, Luo Y (2008) FASEB J (in press)Google Scholar
  82. Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V (2005) Cell Death Differ 12:751–760CrossRefGoogle Scholar
  83. Zalk R, Israelson A, Garty ES, Azoulay-Zohar H, Shoshan-Barmatz V (2005) Biochem J 386:73–83CrossRefGoogle Scholar
  84. Zheng Y, Shi Y, Tian C, Jiang C, Jin H, Chen J, Almasan A, Tang H, Chen Q (2004) Oncogene 23:1239–1247CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Varda Shoshan-Barmatz
    • 1
    • 2
  • Nurit Keinan
    • 1
    • 2
  • Hilal Zaid
    • 1
    • 2
  1. 1.Department of Life SciencesBen-Gurion University of the NegevBeer-ShevaIsrael
  2. 2.The National Institute for Biotechnology in the NegevBen-Gurion University of the NegevBeer-ShevaIsrael

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