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Molecular Basis for Mitochondrial Signaling pp 253–283Cite as

New Insights on the Regulation of Programmed Cell Death by Bcl-2 Family Proteins at the Mitochondria: Physiological and Pathophysiological Implications

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Abstract

Apoptosis is the major form of programmed cell death in animals, playing a crucial role in development and tissue homeostasis. Alterations of apoptosis are involved in major pathologies such as cancers and neurodegenerative diseases. The group of proteins known as Bcl-2 family members are at the core of the implementation of this process, to the point that any cancer study almost compulsorily follows the expression of these proteins. For long, the literature about the molecular aspects underlying their function has often been contradictory, if not overly simplified. However, recent breakthroughs have been obtained with structural and imaging methods, offering the opportunity to shed light on many elusive and hardly understandable observations made in the last 20 years, starting when investigators recognized the connection between Bcl-2 family members and mitochondria. This survey does not intend to be an exhaustive review of the large amount of literature on Bcl-2 family members. Rather, we would like to highlight issues that have been somewhat overlooked in the mainstream literature and that might deserve more attention in the light of recent advances. As mitochondriologists have moved toward the field of apoptosis, our views might be different from the ones of many of our colleagues who have done the reverse journey. Our wish is that some of our readers will find them interesting enough to embark upon studying this exciting and fascinating family of proteins.

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References

  • Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337

    Article  Google Scholar 

  • 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 276:11615–11623

    Article  Google Scholar 

  • Aouacheria A, Rech De Laval V, Combet C, Hardwick JM (2013) Evolution of Bcl-2 homology motifs: homology versus homoplasy. Trends Cell Biol 23:103–111

    Article  Google Scholar 

  • Arnaud E, Ferri KF, Thibaut J, Haftek-Terreau Z, Aouacheria A, Le Guellec D, Lorca T, Gillet G (2006) The zebrafish Bcl-2 homologue Nrz controls development during somitogenesis and gastrulation via apoptosis-dependent and -independent mechanisms. Cell Death Differ 13:1128–1137

    Article  Google Scholar 

  • Arokium H, Camougrand N, Vallette FM, Manon S (2004) Studies of the interaction of substituted mutants of BAX with yeast mitochondria reveal that the C-terminal hydrophobic alpha-helix is a second ART sequence and plays a role in the interaction with anti-apoptotic BCL-xL. J Biol Chem 279:52566–52573

    Article  Google Scholar 

  • Arokium H, Ouerfelli H, Velours G, Camougrand N, Vallette FM, Manon S (2007) Substitutions of potentially phosphorylatable serine residues of Bax reveal how they may regulate its interaction with mitochondria. J Biol Chem 282:35104–35112

    Article  Google Scholar 

  • Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662

    Article  ADS  Google Scholar 

  • Bellot G, Cartron PF, Er E, Oliver L, Juin P, Armstrong LC, Bornstein P, Mihara K, Manon S, Vallette FM (2007) TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax. Cell Death Differ 14:785–794

    Article  Google Scholar 

  • Berman SB, Chen YB, Qi B, Mccaffery JM, Rucker EB 3rd, Goebbels S, Nave KA, Arnold BA, Jonas EA, Pineda FJ, Hardwick JM (2009) Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 184:707–719

    Article  Google Scholar 

  • Bleicken S, Jeschke G, Stegmueller C, Salvador-Gallego R, Garcia-Saez AJ, Bordignon E (2014) Structural model of active Bax at the membrane. Mol Cell 56:496–505

    Article  Google Scholar 

  • Breitschopf K, Zeiher AM, Dimmeler S (2000) Ubiquitin-mediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction. J Biol Chem 275:21648–21652

    Article  Google Scholar 

  • Buttner S, Ruli D, Vogtle FN, Galluzzi L, Moitzi B, Eisenberg T, Kepp O, Habernig L, Carmona-Gutierrez D, Rockenfeller P, Laun P, Breitenbach M, Khoury C, Frohlich KU, Rechberger G, Meisinger C, Kroemer G, Madeo F (2011) A yeast BH3-only protein mediates the mitochondrial pathway of apoptosis. EMBO J 30:2779–2792

    Article  Google Scholar 

  • 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 280:10587–10598

    Article  Google Scholar 

  • Cartron PF, Bellot G, Oliver L, Grandier-Vazeille X, Manon S, Vallette FM (2008) Bax inserts into the mitochondrial outer membrane by different mechanisms. FEBS Lett 582:3045–3051

    Article  Google Scholar 

  • Castilla C, Congregado B, Chinchon D, Torrubia FJ, Japon MA, Saez C (2006) Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak. Endocrinology 147:4960–4967

    Article  Google Scholar 

  • Cebulski J, Malouin J, Pinches N, Cascio V, Austriaco N (2011) Yeast Bax inhibitor, Bxi1p, is an ER-localized protein that links the unfolded protein response and programmed cell death in Saccharomyces cerevisiae. PLoS One 6:e20882

    Article  ADS  Google Scholar 

  • Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365

    Article  Google Scholar 

  • Chen ZX, Pervaiz S (2010) Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2. Cell Death Differ 17:408–420

    Article  Google Scholar 

  • Chen MC, Gong HY, Cheng CY, Wang JP, Hong JR, Wu JL (2000) Cloning and characterization of a novel nuclear Bcl-2 family protein, zfMcl-1a, in zebrafish embryo. Biochem Biophys Res Commun 279:725–731

    Article  Google Scholar 

  • Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403

    Article  Google Scholar 

  • Chou JJ, Li H, Salvesen GS, Yuan J, Wagner G (1999) Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 96:615–624

    Article  Google Scholar 

  • Colussi PA, Quinn LM, Huang DC, Coombe M, Read SH, Richardson H, Kumar S (2000) Debcl, a proapoptotic Bcl-2 homologue, is a component of the Drosophila melanogaster cell death machinery. J Cell Biol 148:703–714

    Article  Google Scholar 

  • Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM (2013) Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152:519–531

    Article  Google Scholar 

  • Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  Google Scholar 

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  Google Scholar 

  • Dejean LM, Martinez-Caballero S, Guo L, Hughes C, Teijido O, Ducret T, Ichas F, Korsmeyer SJ, Antonsson B, Jonas EA, Kinnally KW (2005) Oligomeric Bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-induced channel. Mol Biol Cell 16:2424–2432

    Article  Google Scholar 

  • Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A (2008) BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood 111:2300–2309

    Article  Google Scholar 

  • Del Mar Martinez-Senac M, Corbalan-Garcia S, Gomez-Fernandez JC (2000) Study of the secondary structure of the C-terminal domain of the antiapoptotic protein bcl-2 and its interaction with model membranes. Biochemistry 39:7744–7752

    Article  Google Scholar 

  • Del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689

    Article  ADS  Google Scholar 

  • Delbridge AR, Strasser A (2015) The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ 22:1071–1080

    Article  Google Scholar 

  • 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 144:891–901

    Article  Google Scholar 

  • Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B, Martinou JC (2001) Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 8:601–611

    Article  Google Scholar 

  • Edlich F, Banerjee S, Suzuki M, Cleland MM, Arnoult D, Wang C, Neutzner A, Tjandra N, Youle RJ (2011) Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell 145:104–116

    Article  Google Scholar 

  • Egle A, Harris AW, Bath ML, O’Reilly L, Cory S (2004) VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103:2276–2283

    Article  Google Scholar 

  • Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44:817–829

    Article  Google Scholar 

  • Farooq M, Kim Y, Im S, Chung E, Hwang S, Sohn M, Kim M, Kim J (2001) Cloning of BNIP3h, a member of proapoptotic BNIP3 family genes. Exp Mol Med 33:169–173

    Article  Google Scholar 

  • Forde JE, Dale TC (2007) Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 64:1930–1944

    Article  Google Scholar 

  • Garcia-Saez AJ, Mingarro I, Perez-Paya E, Salgado J (2004) Membrane-insertion fragments of Bcl-xL, Bax, and Bid. Biochemistry 43:10930–10943

    Article  Google Scholar 

  • 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 279:21085–21095

    Article  Google Scholar 

  • Gautier F, Guillemin Y, Cartron PF, Gallenne T, Cauquil N, Le Diguarher T, Casara P, Vallette FM, Manon S, Hickman JA, Geneste O, Juin P (2011) Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL. Mol Cell Biol 31:832–844

    Article  Google Scholar 

  • Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD (2012) Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol 8:639–645

    Article  Google Scholar 

  • Gimenez-Cassina A, Danial NN (2015) Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. Trends Endocrinol Metab 26:165–175

    Article  Google Scholar 

  • Gimenez-Cassina A, Garcia-Haro L, Choi CS, Osundiji MA, Lane EA, Huang H, Yildirim MA, Szlyk B, Fisher JK, Polak K, Patton E, Wiwczar J, Godes M, Lee DH, Robertson K, Kim S, Kulkarni A, Distefano A, Samuel V, Cline G, Kim YB, Shulman GI, Danial NN (2014) Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab 19:272–284

    Article  Google Scholar 

  • Gold MR, Ingham RJ, Mcleod SJ, Christian SL, Scheid MP, Duronio V, Santos L, Matsuuchi L (2000) Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase. Immunol Rev 176:47–68

    Article  Google Scholar 

  • 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 143:207–215

    Article  Google Scholar 

  • Gross A, Jockel J, Wei MC, Korsmeyer SJ (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 17:3878–3885

    Article  Google Scholar 

  • Grosse L, Wurm CA, Bruser C, Neumann D, Jans DC, Jakobs S (2016) Bax assembles into large ring-like structures remodeling the mitochondrial outer membrane in apoptosis. EMBO J 35:402–413

    Article  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  Google Scholar 

  • Hengartner MO, Horvitz HR (1994) C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76:665–676

    Article  Google Scholar 

  • Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251

    Article  Google Scholar 

  • Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134:703–707

    Article  Google Scholar 

  • Hsu YT, Youle RJ (1997) Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem 272:13829–13834

    Article  Google Scholar 

  • Hsu YT, Youle RJ (1998) Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 273:10777–10783

    Article  Google Scholar 

  • Izquierdo-Garcia JL, Villa P, Kyriazis A, Del Puerto-Nevado L, Perez-Rial S, Rodriguez I, Hernandez N, Ruiz-Cabello J (2011) Descriptive review of current NMR-based metabolomic data analysis packages. Prog Nucl Magn Reson Spectrosc 59:263–270

    Article  Google Scholar 

  • Jho E, Lomvardas S, Costantini F (1999) A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression. Biochem Biophys Res Commun 266:28–35

    Article  Google Scholar 

  • Jonas EA (2014) Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticity. Biochim Biophys Acta 1842:1168–1178

    Article  Google Scholar 

  • Kaufmann T, Schlipf S, Sanz J, Neubert K, Stein R, Borner C (2003) Characterization of the signal that directs Bcl-x(L), but not Bcl-2, to the mitochondrial outer membrane. J Cell Biol 160:53–64

    Article  Google Scholar 

  • Kelekar A, Thompson CB (1998) Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 8:324–330

    Article  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    Article  Google Scholar 

  • Kim TH, Zhao Y, Ding WX, Shin JN, He X, Seo YW, Chen J, Rabinowich H, Amoscato AA, Yin XM (2004) Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release. Mol Biol Cell 15:3061–3072

    Article  Google Scholar 

  • Kissova I, Plamondon LT, Brisson L, Priault M, Renouf V, Schaeffer J, Camougrand N, Manon S (2006) Evaluation of the roles of apoptosis, autophagy, and mitophagy in the loss of plating efficiency induced by Bax expression in yeast. J Biol Chem 281:36187–36197

    Article  Google Scholar 

  • Kratz E, Eimon PM, Mukhyala K, Stern H, Zha J, Strasser A, Hart R, Ashkenazi A (2006) Functional characterization of the Bcl-2 gene family in the zebrafish. Cell Death Differ 13:1631–1640

    Article  Google Scholar 

  • Kvansakul M, Hinds MG (2015) The Bcl-2 family: structures, interactions and targets for drug discovery. Apoptosis 20:136–150

    Article  Google Scholar 

  • Lessene G, Czabotar PE, Colman PM (2008) BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 7:989–1000

    Article  Google Scholar 

  • Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, Baell JB, Colman PM, Deshayes K, Fairbrother WJ, Flygare JA, Gibbons P, Kersten WJ, Kulasegaram S, Moss RM, Parisot JP, Smith BJ, Street IP, Yang H, Huang DC, Watson KG (2013) Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol 9:390–397

    Article  Google Scholar 

  • Letai AG (2008) Diagnosing and exploiting cancer’s addiction to blocks in apoptosis. Nat Rev Cancer 8:121–132

    Article  Google Scholar 

  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676

    Article  ADS  Google Scholar 

  • Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-Mcclure ML, Heidenreich KA (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24:9993–10002

    Article  Google Scholar 

  • Luna-Vargas MP, Chipuk JE (2016) Physiological and pharmacological control of BAK, BAX, and beyond. Trends Cell Biol 26:906

    Article  Google Scholar 

  • Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490

    Article  Google Scholar 

  • Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, Tasdemir E, Pierron G, Troulinaki K, Tavernarakis N, Hickman JA, Geneste O, Kroemer G (2007) Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26:2527–2539

    Article  Google Scholar 

  • Martin M, Beauvoit B, Voisin PJ, Canioni P, Guerin B, Rigoulet M (1998) Energetic and morphological plasticity of C6 glioma cells grown on 3-D support; effect of transient glutamine deprivation. J Bioenerg Biomembr 30:565–578

    Article  Google Scholar 

  • Martinez-Caballero S, Dejean LM, Kinnally MS, Oh KJ, Mannella CA, Kinnally KW (2009) Assembly of the mitochondrial apoptosis-induced channel, MAC. J Biol Chem 284:12235–12245

    Article  Google Scholar 

  • Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031

    Article  ADS  Google Scholar 

  • Maundrell K, Antonsson B, Magnenat E, Camps M, Muda M, Chabert C, Gillieron C, Boschert U, Vial-Knecht E, Martinou JC, Arkinstall S (1997) Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1. J Biol Chem 272:25238–25242

    Article  Google Scholar 

  • Meijerink JP, Van Lieshout EM, Beverloo HB, Van Drunen E, Mensink EJ, Macville M, Pieters R (2005) Novel murine B-cell lymphoma/leukemia model to study BCL2-driven oncogenesis. Int J Cancer 114:917–925

    Article  Google Scholar 

  • Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M, Thompson CB (1997) Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature 385:353–357

    Article  ADS  Google Scholar 

  • Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K (2006) The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell 24:677–688

    Article  Google Scholar 

  • Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274:1393–1418

    Article  Google Scholar 

  • Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SL, Fesik SW (1996) X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381:335–341

    Article  ADS  Google Scholar 

  • Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658

    Article  ADS  Google Scholar 

  • O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17:384–395

    Article  Google Scholar 

  • Oberstein A, Jeffrey PD, Shi Y (2007) Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 282:13123–13132

    Article  Google Scholar 

  • Odunsi K, Wollman RM, Ambrosone CB, Hutson A, Mccann SE, Tammela J, Geisler JP, Miller G, Sellers T, Cliby W, Qian F, Keitz B, Intengan M, Lele S, Alderfer JL (2005) Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics. Int J Cancer 113:782–788

    Article  Google Scholar 

  • Oliver L, Priault M, Tremblais K, Lecabellec M, Meflah K, Manon S, Vallette FM (2000) The substitution of the C-terminus of Bax by that of Bcl-xL does not affect its subcellular localization but abrogates its pro-apoptotic properties. FEBS Lett 487:161–165

    Article  Google Scholar 

  • 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 435:677–681

    Article  ADS  Google Scholar 

  • Ottilie S, Wang Y, Banks S, Chang J, Vigna NJ, Weeks S, Armstrong RC, Fritz LC, Oltersdorf T (1997) Mutational analysis of the interacting cell death regulators CED-9 and CED-4. Cell Death Differ 4:526–533

    Article  Google Scholar 

  • Owens TW, Valentijn AJ, Upton JP, Keeble J, Zhang L, Lindsay j, Zouq NK, Gilmore AP (2009) Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK. Cell Death Differ 16:1551–1562

    Article  Google Scholar 

  • Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    Article  Google Scholar 

  • Pavlov EV, Priault M, Pietkiewicz D, Cheng EH, Antonsson B, Manon S, Korsmeyer SJ, Mannella CA, Kinnally KW (2001) A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast. J Cell Biol 155:725–731

    Article  Google Scholar 

  • Pena JC, Rudin CM, Thompson CB (1998) A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. Cancer Res 58:2111–2116

    Google Scholar 

  • Petros AM, Medek A, Nettesheim DG, Kim DH, Yoon HS, Swift K, Matayoshi ED, Oltersdorf T, Fesik SW (2001) Solution structure of the antiapoptotic protein bcl-2. Proc Natl Acad Sci U S A 98:3012–3017

    Article  ADS  Google Scholar 

  • Petros AM, Olejniczak ET, Fesik SW (2004) Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644:83–94

    Article  Google Scholar 

  • Peyerl FW, Dai S, Murphy GA, Crawford F, White J, Marrack P, Kappler JW (2007) Elucidation of some Bax conformational changes through crystallization of an antibody-peptide complex. Cell Death Differ 14:447–452

    Article  Google Scholar 

  • Priault M, Hue E, Marhuenda F, Pilet P, Oliver L, Vallette FM (2010) Differential dependence on Beclin 1 for the regulation of pro-survival autophagy by Bcl-2 and Bcl-xL in HCT116 colorectal cancer cells. PLoS One 5:e8755

    Article  ADS  Google Scholar 

  • Quinn L, Coombe M, Mills K, Daish T, Colussi P, Kumar S, Richardson H (2003) Buffy, a drosophila Bcl-2 protein, has anti-apoptotic and cell cycle inhibitory functions. EMBO J 22:3568–3579

    Article  Google Scholar 

  • Renault TT, Grandier-Vazeille X, Arokium H, Velours G, Camougrand N, Priault M, Teijido O, Dejean LM, Manon S (2012) The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation and conformation in yeast. FEBS Lett 586:116–121

    Article  Google Scholar 

  • Renault TT, Teijido O, Antonsson B, Dejean LM, Manon S (2013) Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-x(L): keep your friends close but your enemies closer. Int J Biochem Cell Biol 45:64–67

    Article  Google Scholar 

  • Renault TT, Floros KV, Elkholi R, Corrigan KA, Kushnareva Y, Wieder SY, Lindtner C, Serasinghe MN, Asciolla JJ, Buettner C, Newmeyer DD, Chipuk JE (2015a) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell 57:69–82

    Article  Google Scholar 

  • Renault TT, Teijido O, Missire F, Ganesan YT, Velours G, Arokium H, Beaumatin F, Llanos R, Athane A, Camougrand N, Priault M, Antonsson B, Dejean LM, Manon S (2015b) Bcl-xL stimulates Bax relocation to mitochondria and primes cells to ABT-737. Int J Biochem Cell Biol 64:136–146

    Article  Google Scholar 

  • Renault TT, Dejean LM, Manon S (2016) A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2. Mech Ageing Dev 477:33

    Google Scholar 

  • Ross K, Rudel T, Kozjak-Pavlovic V (2009) TOM-independent complex formation of Bax and Bak in mammalian mitochondria during TNFalpha-induced apoptosis. Cell Death Differ 16:697–707

    Article  Google Scholar 

  • 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 368:915–921

    Article  Google Scholar 

  • Salvador-Gallego R, Mund M, Cosentino K, Schneider J, Unsay J, Schraermeyer U, Engelhardt J, Ries J, Garcia-Saez AJ (2016) Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores. EMBO J 35:389–401

    Article  Google Scholar 

  • Sarosiek KA, Letai A (2016) Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics – recent successes, current challenges and future promise. FEBS J 283:3523

    Article  Google Scholar 

  • Schellenberg B, Wang P, Keeble JA, Rodriguez-Enriquez R, Walker S, Owens TW, Foster F, Tanianis-Hughes J, Brennan K, Streuli CH, Gilmore AP (2013) Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell 49:959–971

    Article  Google Scholar 

  • Schendel SL, Xie Z, Montal MO, Matsuyama S, Montal M, Reed JC (1997) Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci U S A 94:5113–5118

    Article  ADS  Google Scholar 

  • Schinzel A, Kaufmann T, Schuler M, Martinalbo J, Grubb D, Borner C (2004) Conformational control of Bax localization and apoptotic activity by Pro168. J Cell Biol 164:1021–1032

    Article  Google Scholar 

  • Schlesinger PH, Gross A, Yin XM, Yamamoto K, Saito M, Waksman G, Korsmeyer SJ (1997) Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. Proc Natl Acad Sci U S A 94:11357–11362

    Article  ADS  Google Scholar 

  • 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 U S A 92:7834–7838

    Article  ADS  Google Scholar 

  • Silva RD, Manon S, Goncalves J, Saraiva L, Corte-Real M (2011) Modulation of Bax mitochondrial insertion and induced cell death in yeast by mammalian protein kinase Calpha. Exp Cell Res 317:781–790

    Article  Google Scholar 

  • Simonyan L, Renault TT, Novais MJ, Sousa MJ, Corte-Real M, Camougrand N, Gonzalez C, Manon S (2016) Regulation of Bax/mitochondria interaction by AKT. FEBS Lett 590:13–21

    Article  Google Scholar 

  • Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19:202–208

    Article  Google Scholar 

  • Subburaj Y, Cosentino K, Axmann M, Pedrueza-Villalmanzo E, Hermann E, Bleicken S, Spatz J, Garcia-Saez AJ (2015) Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species. Nat Commun 6:8042

    Article  ADS  Google Scholar 

  • Suzuki M, Youle RJ, Tjandra N (2000) Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103:645–654

    Article  Google Scholar 

  • Swanson PJ, Kuslak SL, Fang W, Tze L, Gaffney P, Selby S, Hippen KL, Nunez G, Sidman CL, Behrens TW (2004) Fatal acute lymphoblastic leukemia in mice transgenic for B cell-restricted bcl-xL and c-myc. J Immunol 172:6684–6691

    Article  Google Scholar 

  • Tang L, Tron VA, Reed JC, Mah KJ, Krajewska M, Li G, Zhou X, Ho VC, Trotter MJ (1998) Expression of apoptosis regulators in cutaneous malignant melanoma. Clin Cancer Res 4:1865–1871

    Google Scholar 

  • Teijido O, Dejean L (2010) Upregulation of Bcl2 inhibits apoptosis-driven BAX insertion but favors BAX relocalization in mitochondria. FEBS Lett 584:3305–3310

    Article  Google Scholar 

  • Terrano DT, Upreti M, Chambers TC (2010) Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol 30:640–656

    Article  Google Scholar 

  • Todt F, Cakir Z, Reichenbach F, Youle RJ, Edlich F (2013) The C-terminal helix of Bcl-x(L) mediates Bax retrotranslocation from the mitochondria. Cell Death Differ 20:333–342

    Article  Google Scholar 

  • Torcia M, De Chiara G, Nencioni L, Ammendola S, Labardi D, Lucibello M, Rosini P, Marlier LN, Bonini P, Dello Sbarba P, Palamara AT, Zambrano N, Russo T, Garaci E, Cozzolino F (2001) Nerve growth factor inhibits apoptosis in memory B lymphocytes via inactivation of p38 MAPK, prevention of Bcl-2 phosphorylation, and cytochrome c release. J Biol Chem 276:39027–39036

    Article  Google Scholar 

  • Tremblais K, Oliver L, Juin P, Le Cabellec TM, Meflah K, Vallette FM (1999) The C-terminus of bax is not a membrane addressing/anchoring signal. Biochem Biophys Res Commun 260:582–591

    Article  Google Scholar 

  • Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(n18) chromosome translocation. Science 226:1097–1099

    Article  ADS  Google Scholar 

  • Valero JG, Sancey L, Kucharczak J, Guillemin Y, Gimenez D, Prudent J, Gillet G, Salgado J, Coll JL, Aouacheria A (2011) Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells. J Cell Sci 124:556–564

    Article  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  ADS  Google Scholar 

  • Vantieghem A, Xu Y, Assefa Z, Piette J, Vandenheede JR, Merlevede W, De Witte PA, Agostinis P (2002) Phosphorylation of Bcl-2 in G2/M phase-arrested cells following photodynamic therapy with hypericin involves a CDK1-mediated signal and delays the onset of apoptosis. J Biol Chem 277:37718–37731

    Article  Google Scholar 

  • Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, Macgregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730

    Article  ADS  Google Scholar 

  • Westphal D, Kluck RM, Dewson G (2014) Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ 21:196–205

    Article  Google Scholar 

  • Willis SN, Fletcher JI, Kaufmann T, Van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315:856–859

    Article  ADS  Google Scholar 

  • Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ (1997) Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139:1281–1292

    Article  Google Scholar 

  • Xin M, Gao F, May WS, Flagg T, Deng X (2007) Protein kinase Czeta abrogates the proapoptotic function of Bax through phosphorylation. J Biol Chem 282:21268–21277

    Article  Google Scholar 

  • Yamaguchi R, Lartigue L, Perkins G, Scott RT, Dixit A, Kushnareva Y, Kuwana T, Ellisman MH, Newmeyer DD (2008) Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell 31:557–569

    Article  Google Scholar 

  • Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291

    Article  Google Scholar 

  • Yin XM, Oltvai ZN, Korsmeyer SJ (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369:321–323

    Article  ADS  Google Scholar 

  • Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B (2001) PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7:673–682

    Article  Google Scholar 

  • Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377

    Article  Google Scholar 

  • Zha H, Aime-Sempe C, Sato T, Reed JC (1996a) Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 271:7440–7444

    Article  Google Scholar 

  • Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996b) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628

    Article  Google Scholar 

  • Zhang T, Saghatelian A (2013) Emerging roles of lipids in BCL-2 family-regulated apoptosis. Biochim Biophys Acta 1831:1542–1554

    Article  Google Scholar 

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Acknowledgments

The work in the labs of the authors has been supported by the CNRS, the ANR, and the Université de Bordeaux (to S.M.) and by the CSUPERB and the California State University of Fresno (to L.D.). L.D. would also like to thank Dr. Krish Krishnan and Rhaul Llanos from the California State University of Fresno for their help with the NMR experiments presented in Fig. 10.4.

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  1. Department of Chemistry, California State University, Fresno, CA, 93740, USA

    Laurent Dejean

  2. CNRS, Université de Bordeaux, UMR5095, 1 Rue Camille Saint-Saëns, 33077, Bordeaux, France

    Stéphen Manon

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  1. Laurent Dejean
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Correspondence to Laurent Dejean or Stéphen Manon .

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  1. Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Tatiana K. Rostovtseva

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Dejean, L., Manon, S. (2017). New Insights on the Regulation of Programmed Cell Death by Bcl-2 Family Proteins at the Mitochondria: Physiological and Pathophysiological Implications. In: Rostovtseva, T. (eds) Molecular Basis for Mitochondrial Signaling. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-55539-3_10

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