FIGURE 5: Model of dynamic equilibrium for Bax localization and activation.

The model is based on data from the present paper, and from previous papers on the yeast model [20,22], and on mammalian cells [24,26,27].

(1) When Bax is phosphorylated on S184, it is spontaneously mostly located in the cytosol. However, the small fraction that remains in the mitochondrial membrane is able to oligomerize to form a pore that promotes the release of cytochrome c (2).

(3) When Bax is not phosphorylated, it is spontaneously mostly located in the mitochondrial membrane, but is unable to oligomerize to form the pore.

(4) In the presence of Bcl-xL, phosphorylated Bax and Bcl-xL are conveyed together to the membrane where the high stability of the interaction prevents the activation of Bax. Although the process is reversible through retrotranslocation, the system is favored towards Bax mitochondrial localization through the possible dephosphorylation of Bax.

(5) Conversely, in the presence of derepressors of the interaction between Bax and Bcl-xL (BH3-only proteins, such as Bim, or BH3-mimetic molecules, such as ABT-737), Bax is able to form a pore with great efficiency because it is already present in great amount in the membrane (see the discussion in [24]).

20. Xin M, Gao F, May WS, Flagg T and Deng X (2007). Protein kinase Czeta abrogates the proapoptotic function of Bax through phosphorylation. J Biol Chem 282(29):21268-21277. https://doi.org/10.1074/jbc.M701613200

22. Simonyan L, Renault TT, da Costa Novais MJ, Sousa MJ, Côrte-Real M, Camougrand N, Gonzalez C, and Manon S (2016). Regulation of Bax/mitochondria interaction by AKT. FEBS Lett 590(1):13-21. https://doi.org/10.1002/1873-3468.12030

24. Renault TT, Teijido O, Missire F, Ganesan YT, Velours G, Arokium H, Beaumatin F, Llanos R, Athané A, Camougrand N, Priault M, Antonsson B, Dejean LM, and Manon S (2015). Bcl-xL stimulates Bax relocation to mitochondria and primes cells to ABT-737. Int J Biochem Cell Biol 64:136-146. https://doi.org/10.1016/j.biocel.2015.03.020

26. Todt F, Cakir Z, Reichenbach F, Youle RJ and Edlich F (2013). The C-terminal helix of Bcl-x(L) mediates Bax retrotranslocation from the mitochondria. Cell Death Differ 20(2):333-342. https://doi.org/10.1038/cdd.2012.131

27. Schellenberg B1, Wang P, Keeble JA, Rodriguez-Enriquez R, Walker S, Owens TW, Foster F, Tanianis-Hughes J, Brennan K, Streuli CH and Gilmore AP (2013). Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell 49(5):959-971. https://doi.org/10.1016/j.molcel.2012.12.022