title: Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis.
abstract: Intrinsic apoptotic stimuli initiate mammalian cells' apoptotic program by first activating the proteins that have only Bcl-2 homology domain 3 (BH3), such as Bcl-2 interacting mediator of cell death (Bim) and truncated BH3 interacting death domain agonist (tBid), which in turn trigger conformational changes in BCL2-associated X (Bax) and BCL2-antagonist/killer (Bak) proteins that enable oligomer formation on the mitochondria, causing cytochrome c and other apoptogenic proteins in the intermembrane space to leak out. Leaked cytochrome c then initiates apoptotic caspase activation through a well-defined biochemical pathway. However, how oligomerized Bax and Bak cause cytochrome c release from mitochondria remains unknown. We report here the establishment of cell lines in which Bim or tBid can be inducibly expressed to initiate apoptosis in a controlled, quantitative manner. We used these cell lines to examine apoptotic events after Bax and Bak oligomerization but before cytochrome c release. The mitochondrial metalloprotease OMA1 was activated in this system in a Bax- and Bak-dependent fashion. Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. Thus it is clear that oligomerized Bax and Bak trigger apoptosis by causing both the permeabilization of the mitochondrial outer membrane and activation OMA1.
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China; Graduate School of Peking Union Medical College, Beijing 100730, China; and Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China;
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China; Graduate School of Peking Union Medical College, Beijing 100730, China; and Chinese Academy of Medical Sciences, Beijing 100730, China wangxiaodong@nibs.ac.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D055550:Protein Stability; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D008666:Metalloendopeptidases; C477817:molecule metalloprotease-related protein-1, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
keywords: Smac; caspase; membrane potential; permeability