Traveling Bax and forth from mitochondria to control apoptosis

Abstract

Antiapoptotic Bcl-2 proteins on mitochondria inhibit prodeath proteins, such as Bax, which are found primarily in the cytosol. In this issue, Edlich et al., (2011) show that Bax and Bcl-xL interact on the mitochondrial surface and then retrotranslocate to the cytosol, effectively preventing Bax-induced permeabilization of mitochondria.

Figure 1

Bax Movements in Healthy Cells and during Apoptosis In healthy cells, inactive Bax continuously cycles between mitochondria and the cytosol. Bax retrotranslocation requires interaction with an antiapoptotic protein (Bcl-xL, Bcl-2, or Mcl1). Together, these two proteins leave the mitochondrial outer membrane (OM). Once in the cytosol, the complex immediately dissociates. The retrotranslocation process is stimulated by the antiapoptotic proteins Bcl-xL, Bcl-2, or Mcl1 and is inhibited by vMIA, ABT-737, and BH3-only proteins. Upon induction of apoptosis, Bax is directly stimulated by activating BH3-only proteins (e.g., Bid, Bim, or Puma; blue arrow) to expose its C-terminal domain and insert in the mitochondrial OM. During this process, Bax exposes a novel N-terminal epitope (6A7), triggering the formation of foci and release of cytochrome c. Neutralizing BH3-only proteins (or small molecule inhibitors; green rectangle) can indirectly activate Bax by binding and inactivating antiapoptotic proteins. Consequently, Bax accumulates on the mitochondrial OM, where it acquires its active conformation.