Doughnuts, daisy chains and crescent moons: the quest for the elusive apoptotic pore

Abstract

How the two killer proteins Bax and Bak form the putative “apoptotic pore” that is responsible for irrevocably damaging mitochondria leading to cell death during apoptosis is considered the “holy grail” of apoptosis research. Indeed, even whether Bax and Bak form a pore remains contentious largely due to the failure to detect such structures in cells or mitochondria. Two new super‐resolution microscopy studies in this issue of The EMBO Journal now provide tantalising evidence of ring‐like “apoptotic pores” on mitochondria of dying cells and provide new insight into how Bax and Bak bring about a cell's demise.

Figure 1. Forming the Bax apoptotic pore

Bax is normally cytosolic but accumulates on the mitochondrial outer membrane (MOM) during apoptosis. Interaction with BH3‐only proteins downstream of an apoptotic stress leads to drastic conformation change in Bax including exposure of its BH3 domain, exposure of N‐terminal epitopes and dissociation of α1–5 from α6–9. Conformation changes facilitate the self‐association of Bax to initially form symmetrical homodimers involving reciprocal insertion of the exposed BH3 domain into a surface groove on the partner protein. Super‐resolution microscopy has now revealed that these dimers multimerise to form distinct structures in the MOM including lines (daisy chains), arcs (crescent moons) and rings (doughnuts) that puncture the MOM and promote cell death. Whether these structures are distinct or are snapshots of different stages of a forming circular pore is not known. Also whether other mitochondrial proteins (purple) contribute to the pore is unclear. That arcs appear sufficient to permeabilise the MOM and that the pore appears heterogeneous in size support the notion that the pores are lipidic with intercalated lipid headgroups playing an important role. The molecular events that allow dimers to multimerise and the topology of Bax dimers (depicted here in a “side by side” arrangement) in these higher order structures remain unclear.