Holding onto Two Jobs

Abstract

Proteins in the Bcl-2 family are critical to apoptosis, a process of programmed cell death (PCD): In mammals, proapoptotic proteins (such as Bax) stimulate mitochondrial fragmentation, mitochondrial outer membrane permeabilization, and the release of apoptogenic proteins from the mitochondria; antiapoptotic proteins (such as Bcl-2 and Bcl-xL) oppose these processes. In the nematode Caenorhabditis elegans , CED-9, a protein related to Bcl-2, sequesters the caspase-activating protein CED-4 and thereby inhibits PCD (see Estaquier and Arnoult). Noting that Bcl-2 inhibits PCD when expressed in C. elegans , Delivani et al. expressed CED-9 in mammalian cells and found that, although it localized to mitochondria, CED-9 failed to inhibit Bax-induced release of cytochrome c from mitochondria or apoptosis in response to various stimuli. However, CED-9 promoted remodeling of the mitochondrial network into large perinuclear structures and inhibited the mitochondrial fragmentation associated with apoptosis. The C. elegans BH3-only protein EGL-1, which binds to CED-9 and thereby stimulates PCD, promoted mitochondrial fragmentation in mammalian cells (as it does in C. elegans ) and inhibited CED-9-mediated mitochondrial fusion. When coexpressed in mammalian cells, CED-9 immunoprecipitated with Mitofusin-2 (Mfn-2, a human protein that promotes mitochondrial fusion). Similarly, Bcl-2 or Bcl-xL interacted with Mfn-2 when cotransfected into mammalian cells, and Bcl-xL promoted mitochondrial fusion. Thus, the authors suggest that Bcl-2 family proteins have an evolutionarily conserved role in regulating mitochondrial fission and fusion distinct from their conserved role in regulating apoptosis. P. Delivani, C. Adrain, R. C. Taylor, P. J. Duriez, S. J. Martin, Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Mol. Cell 21 , 761-773 (2006). [PubMed] J. Estaquier, D. Arnoult, CED-9 and EGL-1: A duo also regulating mitochondrial network morphology. Mol. Cell 21 , 730-732 (2006). [PubMed]