Therapeutic modulation of apoptosis: targeting the BCL-2 family at the interface of the mitochondrial membrane

Abstract

A vast portion of human disease results when the process of apoptosis is defective. Disorders resulting from inappropriate cell death range from autoimmune and neurodegenerative conditions to heart disease. Conversely, prevention of apoptosis is the hallmark of cancer and confounds the efficacy of cancer therapeutics. In the search for optimal targets that would enable the control of apoptosis, members of the BCL-2 family of anti- and pro-apoptotic factors have figured prominently. Development of BCL-2 antisense approaches, small molecules, and BH3 peptidomimetics has met with both success and failure. Success-because BCL-2 proteins play essential roles in apoptosis. Failure-because single targets for drug development have limited scope. By examining the activity of the BCL-2 proteins in relation to the mitochondrial landscape and drawing attention to the significant mitochondrial membrane alterations that ensue during apoptosis, we demonstrate the need for a broader based multi-disciplinary approach for the design of novel apoptosis-modulating compounds in the treatment of human disease.

Fig. 1

Mitochondrial membranes are sites of dynamic events during apoptosis. (A). In non-apoptotic cells the cytosol contains monomeric BAX (light red), while in the outer mitochondrial membrane (OMM), membrane-associated BAX monomers (dark red) are found in close association with anti-apoptotic proteins like BCL-2 (blue-green) or BCL-XL (green). Membrane-associated BAK (dark red) is found in complex with VDAC2. Soluble BH3-only (lavender) proteins like BAD or BIM are sequestered by distinct regulatory mechanisms in the cytosol. The mitochondrial cristae junction is denoted by the two pores that span both mitochondrial membranes. ATP synthesis proteins (pink) are embedded in the inner mitochondrial membrane (IMM). Cholesterol (yellow) spans both bilayers. Cardiolipin (double red squares) has bound cytochrome c (dark blue) and together these are located in inner face of the IMM. SMAC/Diablo (light blue smiley faces), as examples of mitochondrial apoptotic factors, is found in the intermembrane spaces. (B) In apoptotic cells, cardiolipin (double red squares), flips from the IMM inner leaflet to the OMM outer leaflet, carrying cytochrome c. Initiation of apoptosis activates cytosolic BAX (light red) which is recruited to the OMM to form oligomers (dark red). This is enabled by membrane-associated BAX (dark red) and BAK monomers that are no longer sequestered by BCL-2, BCL-XL or VDAC2 and can act as nuclei for the initiation of BAX/BAK oligomer formation. This process is enabled by soluble BH3 proteins (lavender) that bind to and inactivate BCL-2 (blue-green) and BCL-XL (green). The cristae junction is spanned by BAX/BAK oligomeric complexes and mitochondrial membrane is disrupted, leading to the release of cytochrome c (dark blue) and SMAC/Diablo (light blue) into the cytosol.