Role for CED-9 and Egl-1 as Regulators of Mitochondrial Fission and Fusion Dynamics

Abstract

Bcl-2 family proteins play central roles in apoptosis by regulating the release of mitochondrial intermembrane space proteins such as cytochrome c. Deathpromoting Bcl-2 family members, such as Bax, can promote cytochrome c release and fragmentation of the mitochondrial network, whereas apoptosis-inhibitory members, such as Bcl-2 and Bcl-xL, can antagonize these events. It remains unclear whether CED-9, the worm Bcl-2 relative, can regulate mitochondrial fission/fusion dynamics or the release of proteins from the mitochondrial intermembrane space. Here, we show that CED-9 interacts with Mitofusin-2/fuzzy onions and can promote mitochondrial clustering and dramatic reorganization of mitochondrial networks. Consistent with its ability to neutralize CED-9 function, EGL-1 antagonized CED-9-dependent remodeling of the mitochondrial network. However, CED-9 failed to inhibit mitochondrial cytochrome c release or apoptosis induced by diverse triggers in mammalian cells. These data suggest that the ability to regulate mitochondrial fission/fusion dynamics is an evolutionarily conserved property of the Bcl-2 family.

Mitochondrial dynamics in the regulation of neuronal cell death

“…The fact that Bax alone can induce release of molecules from liposomes, suggests that Bax does not require mitochondria to undergo fission to form pores for the release of proapoptotic proteins [70]. Recent studies in C. elegans [71] have clearly disconnected the fission event from apoptosis where they have shown that cells with completely fragmented mitochondria can survive. Inhibition of fragmentation by downregulation of Drp1 or Fis1 does not inhibit Bax/Bak dependent apoptosis and can only partially inhibit release of cytochrome C [72].…”

“…This suggests that Mfn2 activity may affect mitochondrial recruitment of Bax or Drp1 during cell death. Mfn2 can also interact directly with Ced9 or BclxL in HEK293 cells suggesting a mechanism for crosstalk with antiapoptotic Bcl family proteins [71]. Mfn2 has been shown to modulate metabolism [104,105] and cell cycle [106].…”

Mitochondrial membrane remodeling in apoptosis: an inside story

“…Although initial studies from Youle's laboratory suggested that interfering with the process of mitochondrial fission could delay the release of cytochrome c and consequent apoptosis, 20 subsequent reports suggest that these events may be coincident rather than functionally interconnected. 14,21 Moreover, data from Arnoult et al 14 suggest that cytochrome c release may even occur before any discernable fragmentation of the mitochondrial network. At present, the preponderance of evidence suggests that although Bax and/or Bak activation within the outer mitochondrial membrane can undoubtedly provoke collapse and fragmentation of normal mitochondrial networks, this may not be strictly required for cytochrome c release.…”

“…It is also clear that mitochondrial networks can become extensively fragmented without releasing intermembrane space proteins or provoking apoptosis. 13,21 It has also been proposed that some members of the Bcl-2 family, as a secondary function to their role in regulating apoptosis, may also contribute to mitochondrial fusion and fission dynamics in healthy cells. 21 Interference with the latter function (as a consequence of interaction with proapoptotic Bcl-2 family members) may therefore result in collapse of the mitochondrial network in parallel with the formation of Bax/Bak oligomers that permit escape of proteins from the mitochondrial intermembrane space.…”

Alternate functions of viral regulators of cell death

“…The Bcl-2 homolog encoded by Caenorhabditis elegans, CED-9, was recently found to interact with Mfn2 (mitofusin 2; homolog of yeast fuzzy onion 1/Fzo1), a regulator of mitochondrial fusion. 73 Genetic studies in C. elegans demonstrated that worm Bcl-2, normally an antideath factor, can promote cell death by activating Drp1, a dynamin-like GTPase that was first identified in yeast as a factor that is required for mitochondrial fission. 74,75 The human and yeast homologs of Drp1/Dnm1 also promote programmed cell death in mammalian and yeast cells, respectively.…”