To fuse and to protect. A novel role for CED-9 in mitochondrial morphology reveals an ancient function

Imagine that while walking in your Campus behind an old, gigantic tree you find the Magic Lamp; imagine that the Genius of the Lamp is willing to satisfy only one of your (many) desires; imagine that you are a scientist, that you are working on apoptosis, more specifically on the role of mitochondria in cell death. Well, won't you ask the Genius to let you know ‘Why and when’? Why did Nature choose mitochondria as the main actor of programmed cell death, and when during evolution this happened? Of course you would, but unfortunately Geniuses are on strike for the next two hundred years (at least here in Italy…). So you must stick to Science and look out for experimental evidences that can provide an answer to your question. Apparently this is your lucky day, because a recent paper by Seamus Martin and co-workers is here to help you out.¹

Mitochondria are key organelles in apoptosis. In mammalian cells they orchestrate the amplification of death signals by releasing cytochrome c into the cytosol, where it forms the so-called apoptosome together with the adapter Apaf-1 and procaspase 9. This complex, in cooperation with other factors released from mitochondria, is required for the complete activation of effector caspases.² Anti- and proapoptotic members of the Bcl-2 family negatively or positively regulate this release, ultimately defining the fate of the cell.³ The fine mechanisms controlling the egress of cytochrome c remain a matter of intense debate. A current model postulates that the ‘BH3-only’ subset of proapoptotic Bcl-2 family members senses death signals and transmits them to the ‘multidomain’ proapoptotics like Bax and Bak. These ultimately oligomerize in the mitochondrial outer membrane to generate pathways that grant the physical efflux of cytochrome c and of the other mitochondrial apoptotic cofactors. While such a model appears substantiated by several evidences, how antiapoptotic Bcl-2 family members oppose their proapoptotic counterparts is less clear. It has been proposed that Bcl-2 and Bcl-X_L sequester BH3-only molecules, preventing activation of the multidomain proapoptotics.⁴ Alternatively, antiapoptotic proteins could keep Bax and Bak in an inactive conformation, antagonizing binding to the incoming BH3-only proteins.⁵ Even more debated is how the activation of multidomain proapoptotics results in the release of cytochrome c. It remains unclear whether this process involves only the outer membrane, or also changes in the inner; whether it requires additional mitochondrial cofactors, or Bax and/or Bak are self-sufficient; whether it requires, or it is followed by mitochondrial dysfunction.³

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