BH3 peptides induce mitochondrial fission and cell death in the absence of BAX and BAK.

摘要

The BCL-2 family of proteins plays a key role during the process of apoptosis. Apoptosis is an integral part during embryonic development and also a key process during adult life. Cells deficient of BAX and BAK multi BH3 proteins are resistant to apoptosis, but nevertheless, the knock out of BAX and BAK does not cause embryonic lethality. Thus an interesting question is how cells commit to death in the absence of BAX and BAK. My thesis shows that BH3 peptides corresponding to the death domain of BH3-only proteins, that binds to all pro-survival proteins, induces death in the absence of BAX and BAK. Cell death induced by the BH3 peptides did not cause the release of cytochrome c from isolated mitochondria or in whole cells, however, the BH3 peptides induced a loss in mitochondrial membrane potential. My work further revealed that very early following BH3 peptide treatment, the mitochondria undergo fission in the absence of BAX and BAK. I also demonstrated that the binding of the pro-survival protein BCL-XL to the fission GTPase-dynamin-related protein 1 (DRP-1) increased in the presence of the BH3 only peptides. Interestingly, in C.elegans, BAX and BAK proteins are not present and neutralization of pro-survival by a BH3-only protein induces mitochondrial fission and developmental cell death. My thesis therefore, proposes a model whereby in the absence of BAX and BAK in the mammalian cells, the BH3 peptides engage the pro-survival BCL-2 proteins to regulate mitochondrial fission and cell death.