A New View of the Lethal Apoptotic Pore

Cell death by apoptosis is indispensable for proper development and tissue homeostasis in all multicellular organisms, and its deregulation plays a key role in cancer and many other diseases. A crucial event in apoptosis is the formation of protein-permeable pores in the outer mitochondrial membrane that release cytochrome c and other apoptosis-promoting factors into the cytosol. Research efforts over the past two decades have established that apoptotic pores require BCL-2 family proteins, with the proapoptotic BAX-type proteins being direct effectors of pore formation. Accumulating evidence indicates that other cellular components also cooperate with BCL-2 family members to regulate the apoptotic pore. Despite this knowledge, the molecular pathway leading to apoptotic pore formation at the outer mitochondrial membrane and the precise nature of this outer membrane pore remain enigmatic. In this issue of PLOS Biology, Kushnareva and colleagues describe a novel kinetic analysis of the dynamics of BAX-dependent apoptotic pore formation recapitulated in native mitochondrial outer membranes. Their study reveals the existence of a hitherto unknown outer mitochondrial membrane factor that is critical for BAX-mediated apoptotic pore formation, and challenges the currently popular view that the apoptotic pore is a purely proteinaceous multimeric assembly of BAX proteins. It also supports the notion that membrane remodeling events are implicated in the formation of a lipid-containing apoptotic pore.Apoptosis is the orderly sequence of events that leads to the death of a cell without releasing harmful substances into the surrounding tissue; it is indispensable for normal embryonic development and maintenance of healthy tissues in all multicellular organisms and important in many pathologies. The death of neurons and lymphocytes by apoptosis, for example, contributes to neurodegeneration and AIDS, respectively. By ensuring the death of damaged cells, apoptosis also plays key roles in cancer prevention and in successful cancer treatment. Over 25 years of apoptosis research have led to the broadly accepted notion that mitochondria, traditionally viewed as the “powerhouses” of the cell, are also intimately linked to cell death.Apoptosis can be initiated either by the activation of cell-surface-expressed death receptors or by diverse intracellular signals that impinge on the mitochondria. In vertebrates, the commitment step in the mitochondrial pathway of apoptosis is the assembly of a supramolecular structure called the apoptotic pore in the outer mitochondrial membrane [1]. This outer membrane pore allows for rapid diffusion out of the mitochondria of cytochrome c and other proteins that promote the irreversible dismantling of the cell. Despite intense research efforts, our understanding of the molecular machinery and mechanisms implicated in this crucial aspect of apoptosis is still incomplete.