Item – Theses Canada

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OCLC number
847331978
Author
Satsoura, Dmitri,
Title
Characterization of the molecular mechanism of membrane permeabilization by Bax.
Degree
Ph. D. -- McMaster University, 2010
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2012]
Description
2 microfiches
Notes
Includes bibliographical references.
Abstract
<?Pub Inc> Apoptosis is a fundamental cellular process that helps to maintain tissue homeostasis and regulate cell number during development. Permeabilization of the outer mitochondrial membrane is one of the key steps in this process. Bcl-2 family proteins playa pivotal role in both the regulation and the formation of large pores in the outer mitochondrial membrane. During apoptosis, Bax, a pro-apoptotic member of the Bcl-2 family of proteins, is activated and relocalizes from the cytosol to the outer mitochondrial membrane, where it forms membrane pores that are large enough to release proteins. However, the composition and the mechanism of formation of these pores remain unclear. To address these fundamental questions I used a reconstituted system consisting of mitochondria or liposomes and wild type or fluorescently-tagged Bcl-2 family proteins and a combination of biochemical and fluorescence-based techniques. The results presented in this thesis suggest a mechanism of propagation of mitochondrial membrane permeabilization throughout a cell based upon an observation that tBid, a truncated form of pro-apoptotic Bcl-2 family member Bid, bound to one mitochondrion triggers Bax-mediated permeabilization of another mitochondrion without any bound tBid. In addition, the results presented here suggest that Bax oligomers that form pores in the membrane of mitochondria are very dynamic entities that can change size by recruiting additional Bax molecules, eventually forming oligomers containing at least 20 Bax molecules. Interestingly, binding of Bax to phospholipid membranes is not random but rather partly co-operative, suggesting that Bax is capable of autoactivation. Together these results reveal intricate details of mitochondrial membrane permeabilization by Bax, one of the key steps of the cell death programme.
ISBN
9780494746523
0494746521