The deadly landscape of pro-apoptotic BCL-2 proteins in the outer mitochondrial membrane

Apoptosis is a biological process that removes damaged, excess or infected cells through a genetically controlled mechanism. This process plays a crucial role in organismal development, immunity and tissue homeostasis, and alterations in apoptosis contribute to human diseases including cancer and auto-immunity. In the past two decades, significant efforts have focused on understanding the function of the BCL-2 proteins, a complex family of pro-survival and pro-apoptotic alpha-helical proteins that directly control the mitochondrial pathway of apoptosis. Diverse structural investigations of the BCL-2 family members have broadened our mechanistic understanding of their individual functions. However, an often over-looked aspect of the mitochondrial pathway of apoptosis is how the BCL-2 family specifically interacts with and targets the outer mitochondrial membrane to initiate apoptosis. Structural information on the relationship between the BCL-2 family and the outer mitochondrial membrane is missing; likewise, knowledge of the biophysical mechanisms by which the outer mitochondrial membrane affects and effects apoptosis is lacking. In this mini-review, we provide a current overview of the BCL-2 family members and discuss the latest structural insights into BAK/BAX activation and oligomerization in the context of the outer mitochondrial membrane and mitochondrial biology.