The Executioners of Mitochondrial Apoptosis: Structures, Mechanisms, and Therapeutic Advances of BAX, BAK, and BOK

Abstract

ABSTRACT The BCL‐2 family effector proteins BAX, BAK, and BOK are pivotal regulators of the mitochondrial apoptosis pathway. They act as the ultimate executioners responsible for the irreversible step of mitochondrial outer membrane permeabilization. Their molecular conformations and dynamic changes determine the initiation of mitochondrial apoptosis and are intimately linked to the pharmacological efficacy of apoptotic modulators. This review provides a comprehensive analysis of the intricate structural mechanisms that govern activation, oligomerization, and pore formation of BAX, BAK, and BOK. Furthermore, this review summarizes the crucial sites involved in regulating their activity, as well as the latest advances in pharmacological strategies aimed at directly modulating their activity. These contents offer valuable insights for the development of apoptosis‐based therapies and drug targets.