Bcl-2 Family Members and the Mitochondrial Import Machineries: The Roads to Death

Abstract

The localization of Bcl-2 family members at the mitochondrial outer membrane (MOM) is a crucial step in the implementation of apoptosis. We review evidence showing the role of the components of the mitochondrial import machineries (translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM)) in the mitochondrial localization of Bcl-2 family members and how these machineries regulate the function of pro- and anti-apoptotic proteins in resting cells and in cells committed into apoptosis.

Keywords: apoptosis; bcl-2 family; mitochondrial import machineries.

Figure 1

Protein import and insertion in mammalian mitochondrial outer membrane. Overview of the mitochondrial outer membrane (MOM) protein import. Alpha-helix structured proteins are recognized by outer membrane receptors such as TOM70/TOM20/TOM22 either co- or post-translationally. Incorporation into MOM requires a multi-protein structure containing TOM40 and TOM22 plus small TOMs (TOM5, TOM6, and TOM7) (grey structures, left). β-Barrel proteins use a different system called the sorting assembly machinery (SAM) (black blocks, right), which includes 3 proteins in yeast (SAM 35, SAM37, and Sam 50). SAM35 and Sam37 act as peripheral receptors for proteins, while SAM50 is considered as the import/assembly channel. In mammalian mitochondria, metaxin 1 and metaxin 2 (MTX1 and MTX2) are 2 orthologs of SAM 35 and SAM37, and a protein similar to SAM50 has been found. Of note, TOM40 is a substrate of SAM50.

Figure 2

Interplay between Bcl-2 family members. The interaction between antiapoptotic and pro-apoptotic Bcl-2 proteins prevent pore formation and caspase activation responsible for cell death. BH3-only proteins can either counteract the interaction between anti- and pro-apoptotic proteins or directly activate pro-apoptotic proteins.

Figure 3

Representation of the interaction network between Bcl-2 family members and the mitochondrial import machinery components during apoptosis commitment. Upper, interaction network in resting cells; bottom, network modifications in apoptosis-primed cells. The ER to mitochondria transfer of lipid, such as PS and ceramides, occurs at ER–mitochondria contact sites [130] and may contribute to the activation of Bax and/or to the formation of the pore. Local concentration of Ca2+/Mg2+ also participates in the regulation of Bcl-2 family interaction with the MOM [126]. The kinase AKT plays a major role both in the reprogramming of mitochondrial metabolism in cancer cells and in the activation of surviving signaling pathways, which includes its capacity to phosphorylate both Bad and Bax ([131], for review). Further, a fraction of active AKT and of its isoforms displays a mitochondrial localization [132,133]. Bax and Bak are the effectors of the MOMP. It is thus quite evident that their interaction with mitochondrial receptors enhances their pro-apoptotic function.