, Volume 12, Issue 5, pp 887–896 | Cite as

Bax activation and mitochondrial insertion during apoptosis

  • Lisenn Lalier
  • Pierre-François Cartron
  • Philippe Juin
  • Svetlana Nedelkina
  • Stephen Manon
  • Burkhart Bechinger
  • François M. ValletteEmail author


The mitochondrial apoptotic pathway is a highly regulated biological mechanism which determines cell fate. It is defined as a cascade of events, going from an apoptotic stimulus to the MOM permeabilization, resulting in the activation of the so-called executive phase. This pathway is very often altered in cancer cells.

The mitochondrial permeabilization is under the control of the Bcl-2 family of proteins (pBcls). These proteins share one to four homology domains (designed BH1-4) with Bcl-2, and are susceptible of homo- and/or hetero-dimerization. In spite of a poor amino-acid sequence homology, these proteins exhibit very similar tertiary structures. Strikingly, while some of these proteins are anti-apoptotic, the others are pro-apoptotic. Pro-apoptotic proteins are further divided in two sub-classes: multi-domains proteins, among which Bax and Bak, which exhibit BH1-3 domains, and BH3-only proteins (or BOPs). Schematically, BOPs and anti-apoptotic proteins antagonistically regulate the activation of the multi-domain proteins Bax and Bak and their oligomerization in the MOM, the latter process being responsible for the apoptotic mitochondrial permeabilization.

Considering the critical role of Bax in cancer cells apoptosis, we focus in this review on the molecular events of Bax activation through its interaction with the other proteins from the Bcl-2 family. The mechanism by which Bax triggers the MOM permeabilization once activated will be discussed in some other reviews in this special issue.


Apoptosis Mitochondria Bcl-2 family 



BH3 only proteins


proteins of the Bcl-2 family


mitochondrial outer membrane


Apoptosis Regulating Target domain


C-terminal end


N-terminal end


Cytosolic Locked In Conformation


Cytochrome c Liberation Associated Conformation


  1. 1.
    Adams JM, Cory S (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26:61–66PubMedCrossRefGoogle Scholar
  2. 2.
    Er E, Oliver L, Cartron P-F, Juin P, Manon S, Vallette FM (2006) Mitochondria as the target of the pro-apoptotic protein Bax. Biochimica et Biophysica Acta (BBA)—Bioenergetics 1757:1301–1311CrossRefGoogle Scholar
  3. 3.
    Cartron PF, Juin P, Oliver L, Meflah K, Vallette FM (2003) Impact of proapoptotic proteins Bax and Bak in tumor progression and response to treatment. Expert Rev Anticancer Ther 3:563–570PubMedCrossRefGoogle Scholar
  4. 4.
    Suzuki M, Youle RJ, Tjandra N (2000) Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103:645–654PubMedCrossRefGoogle Scholar
  5. 5.
    Petros AM, Olejniczak ET, Fesik SW (2004) Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644:83–94PubMedCrossRefGoogle Scholar
  6. 6.
    Wolter KG, Hsu Y-T, Smith CL, Nechushtan A, Xi X-G, Youle RJ (1997) Movement of Bax from the Cytosol to Mitochondria during Apoptosis. J Cell Biol 139:1281–1292PubMedCrossRefGoogle Scholar
  7. 7.
    Hsu YT, Youle RJ (1998) Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 273:10777–10783PubMedCrossRefGoogle Scholar
  8. 8.
    Hsu YT, Youle RJ (1997) Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem 272:13829–13834PubMedCrossRefGoogle Scholar
  9. 9.
    Hsu YT, Wolter KG, Youle RJ (1997) Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci USA 94:3668–3672PubMedCrossRefGoogle Scholar
  10. 10.
    Cartron PF, Oliver L, Mayat E, Meflah K, Vallette FM (2004) Impact of pH on Bax a conformation, oligomerization and mitochondrial integration. FEBS Lett 578:41–46PubMedCrossRefGoogle Scholar
  11. 11.
    Cartron PF, Arokium H, Oliver L, Meflah K, Manon S, Vallette FM (2005) Distinct domains control the addressing and the insertion of Bax into mitochondria. J Biol Chem 280:10587–10598PubMedCrossRefGoogle Scholar
  12. 12.
    Makin GW, Corfe BM, Griffiths GJ, Thistlethwaite A, Hickman JA, Dive C (2001) Damage-induced Bax N-terminal change, translocation to mitochondria and formation of Bax dimers/complexes occur regardless of cell fate. Embo J 20:6306–6315PubMedCrossRefGoogle Scholar
  13. 13.
    Cartron P-F, Priault M, Oliver L, Meflah K, Manon S, Vallette FM (2003) The N-terminal end of Bax contains a mitochondrial-targeting signal. J Biol Chem 278:11633–11641PubMedCrossRefGoogle Scholar
  14. 14.
    Goping IS, Gross A, Lavoie JN, Nguyen M, Jemmerson R, Roth K, Korsmeyer SJ, Shore GC (1998) Regulated targeting of BAX to mitochondria. J Cell Biol 143:207–215PubMedCrossRefGoogle Scholar
  15. 15.
    Wang K, Gross A, Waksman G, Korsmeyer SJ (1998) Mutagenesis of the BH3 domain of BAX identifies residues critical for simerization and killing. Mol Cell Biol 18:6083–6089PubMedGoogle Scholar
  16. 16.
    Otter I, Conus S, Ravn U, Rager M, Olivier R, Monney L, Fabbro D, Borner C (1998) The binding properties and biological activities of Bcl-2 and Bax in cells exposed to apoptotic stimuli. J Biol Chem 273:6110–6120PubMedCrossRefGoogle Scholar
  17. 17.
    Conus S, Kaufmann T, Fellay I, Otter I, Rosse T, Borner C (2000) Bcl-2 is a monomeric protein: prevention of homodimerization by structural constraints. Embo J 19:1534–1544PubMedCrossRefGoogle Scholar
  18. 18.
    Moreau C, Cartron PF, Hunt A, Meflah K, Green DR, Evan G, Vallette FM, Juin P (2003) Minimal BH3 peptides promote cell death by antagonizing anti-apoptotic proteins. J Biol Chem 278:19426–19435PubMedCrossRefGoogle Scholar
  19. 19.
    Nouraini S, Six E, Matsuyama S, Krajewski S, Reed JC (2000) The putative pore-forming domain of Bax regulates mitochondrial localization and interaction with Bcl-X(L). Mol Cell Biol 20:1604–1615PubMedCrossRefGoogle Scholar
  20. 20.
    Annis MG, Soucie EL, Dlugosz PJ, Cruz-Aguado JA, Penn LZ, Leber B, Andrews DW (2005) Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. Embo J 24:2096–2103PubMedCrossRefGoogle Scholar
  21. 21.
    Garcia-Saez AJ, Coraiola M, Serra MD, Mingarro I, Muller P, Salgado J (2006) Peptides corresponding to helices 5 and 6 of Bax can independently form large lipid pores. FEBS J 273:971–981PubMedCrossRefGoogle Scholar
  22. 22.
    Schendel SL, Montal M, Reed JC (1998) Bcl-2 family proteins as ion-channels. Cell Death Differ 5:372–380PubMedCrossRefGoogle Scholar
  23. 23.
    Nechushtan A, Smith CL, Hsu YT, Youle RJ (1999) Conformation of the Bax C-terminus regulates subcellular location and cell death. Embo J 18:2330–2341PubMedCrossRefGoogle Scholar
  24. 24.
    Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM (2004) Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 279:21085–21095PubMedCrossRefGoogle Scholar
  25. 25.
    Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC (2000) Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 345 (Pt 2):271–278PubMedCrossRefGoogle Scholar
  26. 26.
    Khaled AR, Kim K, Hofmeister R, Muegge K, Durum SK (1999) Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH. Proc Natl Acad Sci USA 96:14476–14481PubMedCrossRefGoogle Scholar
  27. 27.
    Garcia-Saez AJ, Mingarro I, Perez-Paya E, Salgado J (2004) Membrane-insertion fragments of Bcl-xL, Bax, and Bid. Biochemistry 43:10930–10943PubMedCrossRefGoogle Scholar
  28. 28.
    Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111:331–342PubMedCrossRefGoogle Scholar
  29. 29.
    Antonsson B, Montessuit S, Sanchez B, Martinou JC (2001) Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem 276:11615–11623PubMedCrossRefGoogle Scholar
  30. 30.
    Yethon JA, Epand RF, Leber B, Epand RM, Andrews DW (2003) Interaction with a membrane surface triggers a reversible conformational change in Bax normally associated with induction of apoptosis. J Biol Chem 278:48935–48941PubMedCrossRefGoogle Scholar
  31. 31.
    Esposti MD, Dive C (2003) Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun 304:455–461PubMedCrossRefGoogle Scholar
  32. 32.
    Roucou X, Montessuit S, Antonsson B, Martinou JC (2002) Bax oligomerization in mitochondrial membranes requires tBid (caspase-8-cleaved Bid) and a mitochondrial protein. Biochem J 368:915–921PubMedCrossRefGoogle Scholar
  33. 33.
    Cartron PF, Oliver L, Martin S, Moreau C, LeCabellec MT, Jezequel P, Meflah K, Vallette FM (2002) The expression of a new variant of the pro-apoptotic molecule Bax, Baxpsi, is correlated with an increased survival of glioblastoma multiforme patients. Hum Mol Genet 11:675–687PubMedCrossRefGoogle Scholar
  34. 34.
    Cartron PF, Gallenne T, Bougras G, Gautier F, Manero F, Vusio P, Meflah K, Vallette FM, Juin P (2004) The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol Cell 16:807–818PubMedCrossRefGoogle Scholar
  35. 35.
    Juin P, Cartron PF, Vallette FM (2005) Activation of Bax by BH3 domains during apoptosis. Cell Cycle 4:637–642PubMedGoogle Scholar
  36. 36.
    Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC (1999) Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 144:891–901PubMedCrossRefGoogle Scholar
  37. 37.
    Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20:929–935PubMedCrossRefGoogle Scholar
  38. 38.
    Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183–192PubMedCrossRefGoogle Scholar
  39. 39.
    Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ (1996) BID: A novel BH3 domain-only death agonist. Genes Dev 10:2859–2869PubMedGoogle Scholar
  40. 40.
    Terrones O, Antonsson B, Yamaguchi H, Wang HG, Liu J, Lee RM, Herrmann A, Basanez G (2004) Lipidic pore formation by the concerted action of proapoptotic BAX and tBID. J Biol Chem 279:30081–30091PubMedCrossRefGoogle Scholar
  41. 41.
    Cartron P-F, Moreau C, Oliver L, Mayat E, Meflah K, Vallette FM (2002) Involvement of the N-terminus of Bax in its intracellular localization and function. FEBS Lett 512:95–100PubMedCrossRefGoogle Scholar
  42. 42.
    Cartron PF, Gallenne T, Bougras G, Gautier F, Manero F, Vusio P, Khaled M, Vallette FM, Juin P (2004) The first helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins BID and PUMA. Mol Cell 16:807–818PubMedCrossRefGoogle Scholar
  43. 43.
    Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (1997) Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275:983–986PubMedCrossRefGoogle Scholar
  44. 44.
    Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci USA 92:7834–7838PubMedCrossRefGoogle Scholar
  45. 45.
    Zha H, Aime-Sempe C, Sato T, Reed JC (1996) Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 271:7440–7444PubMedCrossRefGoogle Scholar
  46. 46.
    Zha H, Reed JC (1997) Heterodimerization-independent functions of cell death regulatory proteins Bax and Bcl-2 in yeast and mammalian cells. J Biol Chem 272:31482–31488PubMedCrossRefGoogle Scholar
  47. 47.
    Hirotani M, Zhang Y, Fujita N, Naito M, Tsuruo T (1999) NH2-terminal BH4 domain of Bcl-2 is functional for heterodimerization with Bax and inhibition of apoptosis. J Biol Chem 274:20415–20420PubMedCrossRefGoogle Scholar
  48. 48.
    Minn AJ, Kettlun CS, Liang H, Kelekar A, Heiden MGV, Chang BS, Fesik SW, Fill M, Thompson CB (1999) Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms. Embo J 18:632–643PubMedCrossRefGoogle Scholar
  49. 49.
    Dlugosz PJ, Billen LP, Annis MG, Zhu W, Zhang Z, Lin J, Leber B, Andrews DW (2006) Bcl-2 changes conformation to inhibit Bax oligomerization. Embo J 25:2287–2296PubMedCrossRefGoogle Scholar
  50. 50.
    Jeong SY, Gaume B, Lee YJ, Hsu YT, Ryu SW, Yoon SH, Youle RJ (2004) Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers. Embo J 23:2146–2155PubMedCrossRefGoogle Scholar
  51. 51.
    Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3:173–182PubMedCrossRefGoogle Scholar
  52. 52.
    Vieira HL, Boya P, Cohen I, El Hamel C, Haouzi D, Druillenec S, Belzacq AS, Brenner C, Roques B, Kroemer G (2002) Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-X(L). Oncogene 21:1963–1977PubMedCrossRefGoogle Scholar
  53. 53.
    Yin H, Lee GI, Sedey KA, Rodriguez JM, Wang HG, Sebti SM, Hamilton AD (2005) Terephthalamide derivatives as mimetics of helical peptides: disruption of the Bcl-x(L)/Bak interaction. J Am Chem Soc 127:5463–5468PubMedCrossRefGoogle Scholar
  54. 54.
    Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681PubMedCrossRefGoogle Scholar
  55. 55.
    Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3:173–182PubMedCrossRefGoogle Scholar
  56. 56.
    D’Alessio M, De Nicola M, Coppola S, Gualandi G, Pugliese L, Cerella C, Cristofanon S, Civitareale P, Ciriolo MR, Bergamaschi A, Magrini A, Ghibelli L (2005) Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. Faseb J 19:1504–1506PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2007

Authors and Affiliations

  • Lisenn Lalier
    • 1
    • 2
  • Pierre-François Cartron
    • 1
    • 2
  • Philippe Juin
    • 1
    • 2
  • Svetlana Nedelkina
    • 3
    • 4
  • Stephen Manon
    • 5
    • 6
  • Burkhart Bechinger
    • 3
    • 4
  • François M. Vallette
    • 1
    • 2
    • 7
    Email author
  1. 1.INSERM U601NantesFrance
  2. 2.Université de Nantes, Faculté de MédecineNantesFrance
  3. 3.CNRS LC3-UMR7177StrasbourgFrance
  4. 4.Université Louis PasteurInstitut/Faculté de ChimieStrasbourgFrance
  5. 5.Institut de Biochimie et GénétiqueBordeauxFrance
  6. 6.Université de Bordeaux 2BordeauxFrance
  7. 7.INSERM U601, Université de Nantes, Faculté de MédecineNantes. Cedex 01France

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