Please cite this article in press as: Renault TT, et al. 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 (2012), http://dx.doi.org/10.1016/j.biocel.2012.09.022 ARTICLE IN PRESS G Model BC-3859; No. of Pages 4 The International Journal of Biochemistry & Cell Biology xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect The International Journal of Biochemistry & Cell Biology journa l h o me page: www.elsevier.com/locate/biocel Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-x L : Keep your friends close but your enemies closer  Thibaud T. Renault a,b,1 , Oscar Teijido c,2 , Bruno Antonsson d , Laurent M. Dejean e,∗ , Stéphen Manon a,b,∗∗ a CNRS, Institut de Biochimie et de Génétique Cellulaires, UMR5095, 1 rue Camille Saint-Saëns, 33077 Bordeaux, France b Université Bordeaux Ségalen, Institut de Biochimie et de Génétique Cellulaires, UMR5095, 1 rue Camille Saint-Saëns, 33077 Bordeaux, France c New-York University, Department of Basic Sciences, College of Dentistry, New York, NY 10010, USA d Merck Serono S.A., Geneva Research Center, Department of Protein and Cell Sciences, 9 Chemin des Mines, 1202 Geneva, Switzerland e California State University of Fresno, Department of Chemistry, 2555 E. San Ramon, Fresno, CA 93740, USA a r t i c l e i n f o Article history: Available online xxx Keywords: Bax Bcl-2 family Mitochondria Apoptosis a b s t r a c t Bax-induced mitochondrial outer membrane permeabilization (MOMP) is considered as one of the key control switches of apoptosis. MOMP requires Bax relocation to and insertion into the outer mitochondrial membrane to oligomerize and form pores allowing the release of apoptogenic factors such as cytochrome c. Even if these essential steps are now well-defined, it is necessary to better understand the molecular changes underlying the switch between inactive Bax and active (pore-forming) Bax. One of the ongoing issues is to determine whether Bax mitochondrial translocation is a critical step in the control of Bax activation or if this control is carried by latter regulatory steps. In this focus article we discuss recent data suggesting that although Bcl-2 and Bcl-x L block the MOMP, they can also regulate the mitochondrial Bax content. A new model in which Bax inhibition by Bcl-x L occurs at the immediate proximity of the outer mitochondrial membrane is also discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction Mitochondrial outer membrane permeabilization (MOMP) is essential for the regulation of the apoptotic process through the release of killing effectors from mitochondria to cytosol (cytochrome c, Smac/Diablo, Omi/Htra2, etc.). The proteins of the Bcl-2 family are the main regulators of this deadly switch and the understanding of their function has been the focus of intensive studies for more than 20 years. So far, the function of Bcl-2 pro- teins is well understood (Adams and Cory, 2007). Bax and Bak are the direct pro-apoptotic effectors of MOMP as they can translocate and/or insert into the outer mitochondrial membrane, oligomerize  This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adap- tation and therapy. ∗ Corresponding author. ∗∗ Corresponding author at: CNRS, Institut de Biochimie et de Génétique Cellu- laires, UMR5095, 1 rue Camille Saint-Saëns, 33077 Bordeaux, France. Tel.: +33 556999045. E-mail addresses: ldejean@csufresno.edu (L.M. Dejean), manon@ibgc.cnrs.fr (S. Manon). 1 Present address: Mount Sinai School of Medicine, Department of Oncological Sciences, The Tisch Cancer Institute, One Gustave L. Levy Place, Box 1130, New York, NY 10029, USA. 2 Present address: NIH, NICHD, 9 Memorial Dr Room 1N124, MSC 0924 Bethesda, MD 20892-0924, USA. and form pores (Renault and Manon, 2011; Westphal et al., 2011). Whereas Bak has a constitutive mitochondrial localization in healthy cells, Bax is mostly cytosolic, awaiting for activation sig- nals that will trigger its translocation to mitochondria and further activation (Hsu et al., 1997). In the classical model, the antiapop- totic members of the family such as Bcl-2 or Bcl-x L inhibit Bax and Bak activation through a direct interaction involving the so- called BH domains (the Bcl-2 homology domains, which define both the structural and the functional homology patterns within the Bcl-2 family) (Oltvai et al., 1993; Sedlak et al., 1995; Wang et al., 1998). In this model, Bax activation is favoured by the proapoptotic BH3-only proteins. These proteins can act both as direct activators of Bax by interacting directly with Bax (e.g. tBid, Bim, PUMA) or as derepressors (e.g. Bad, Noxa) by interacting with antiapoptotic members of the Bcl-2 family (Adams and Cory, 2007). However, recent data, discussed below, have challenged this model and sug- gest that Bcl-2 and Bcl-x L have an active role in the course of Bax activation. 2. Bax mitochondrial localization and MOMP Despite Bax is mostly reported as being cytosolic in non- apoptotic cells and then mitochondrial upon apoptosis induction, there is no absolute correlation between its relocation to mitochon- dria and subsequent activation leading to MOMP. Several works 1357-2725/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biocel.2012.09.022