Abstract
The proteins of the Bcl-2 family have a crucial role in mitochondrial outer membrane permeabilization during apoptosis and in the regulation of mitochondrial dynamics. Current models consider that Bax forms toroidal pores at mitochondria that are responsible for the release of cytochrome c, whereas Bcl-xL inhibits pore formation. However, how Bcl-2 proteins regulate mitochondrial fission and fusion remains poorly understood. By using a systematic analysis at the single vesicle level, we found that cBid, Bax and Bcl-xL are able to remodel membranes in different ways. cBid and Bax induced a reduction in vesicle size likely related to membrane tethering, budding and fission, besides membrane permeabilization. Moreover, they are preferentially located at highly curved membranes. In contrast, Bcl-xL not only counterbalanced pore formation but also membrane budding and fission. Our findings support a mechanism of action by which cBid and Bax induce or stabilize highly curved membranes including non-lamellar structures. This molecular activity reduces the energy for membrane remodeling, which is a necessary step in toroidal pore formation, as well as membrane fission and fusion, and provides a common mechanism that links the two main functions of Bcl-2 proteins.
Highlights
The mitochondrial pathway of apoptosis results in the permeabilization of the mitochondrial outer membrane (MOM) and in the fragmentation of the tubular mitochondrial network
Our findings suggest that the functional roles of Bcl-2 proteins in MOM permeabilization and mitochondrial shape are linked by their ability to stabilize unfavorable membrane structures
We systematically investigated the effect of different Bcl-2 proteins on membrane structure
Summary
The mitochondrial pathway of apoptosis results in the permeabilization of the mitochondrial outer membrane (MOM) and in the fragmentation of the tubular mitochondrial network. Membrane fission and fusion are lipid-mediated events that proceed through highly curved and energetically unfavorable, non-lamellar membrane structures.[35,36,37,38] The formation of toroidal pores, like those formed by Bax and Bak,[39,40,41,42,43,44] involves similar structures.[45,46] As the Bcl-2 proteins affect both toroidal pore formation and mitochondrial dynamics, it is a reasonable hypothesis that both processes are promoted by a common underlying activity. Our findings suggest that the functional roles of Bcl-2 proteins in MOM permeabilization and mitochondrial shape are linked by their ability to stabilize unfavorable membrane structures
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