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Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis

Proceedings of the National Academy of Sciences of the United States of America, 2014, Vol.111(41), pp.14782-14787 [Tạp chí có phản biện]

ISSN: 0027-8424

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  • Nhan đề:
    Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis
  • Là 1 phần của: Proceedings of the National Academy of Sciences of the United States of America, 2014, Vol.111(41), pp.14782-14787
  • Mô tả: 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.
    Significance The release of cytochrome c from its normal intermembrane space in mitochondria marks the initiation of apoptosis in mammalian cells. The process is triggered by the aggregation of B-cell leukemia/lymphoma 2 (BCL2)-associated X (Bax) and BCL2-antagonist/killer (Bak) proteins on the surface of mitochondria. We found that a mitochondrial inner membrane protease, OMA1 (overlapping activity with m -AAA protease), is specifically activated and is responsible for cleaving another inner membrane protein, optical nerve atrophy 1 (OPA1), upon Bax/Bak aggregation. The cleavage of OPA1 triggers the remodeling of mitochondrial cristae, allowing the majority of cytochrome c inside the cristae to be released. This finding provided a more comprehensive understanding of this critical molecular event during apoptosis. ; p. 14782-14787.
  • Nơi xuất bản: National Academy of Sciences
  • Năm xuất bản: 2014
  • Ngôn ngữ: English
  • Số nhận dạng: ISSN: 0027-8424

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