Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-xL: keep your friends close but your enemies closer

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-xL block the MOMP, they can also regulate the mitochondrial Bax content. A new model in which Bax inhibition by Bcl-xL 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.