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 α‐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. The mitochondrial pathway of apoptosis is initiated by a member of the pro‐apoptotic BCL‐2 family, BAX. BAX activation occurs via a transient interaction with direct activator BH3‐only proteins (e.g., BID). This leads to the release of BAX helices α1 and α9, insertion of BAX α9 into the outer mitochondrial membrane (OMM), and BAX oligomerization. While interactions between BAX and BH3‐only proteins have received much attention in the last two decades, recent findings reveal mitochondrial components (e.g., shape, size and composition) govern BAX conformations leading to its activation. In this mini‐review, we discuss the latest structural insights of BAX activation and oligomerization in the context of the mitochondrial network.