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Mitochondrial membrane permeabilisation by Bax/Bak
Mauro Degli Esposti1, Caroline Dive
1Cancer Research UK Cellular and Molecular Pharmacology Group, School of Biological Sciences, University of Manchester, G38 Stopford Building, Oxford Road, Manchester M134 9PT, UK.
Abstract:
Recent studies on cells derived from mice deficient in both multi-domain pro-apoptotic genes of the Bcl-2 family, Bax and Bak, suggest that one or other of these proteins are required for the release of apoptogens such as cytochrome c from mitochondria. In addition BH-3 only proteins of this family such as Bid are suggested to act as critical death inducing ligands via interactions with pro- and anti-apoptotic Bcl-2 family proteins with Bax or Bak at the mitochondrial surface. Despite this increase in knowledge it remains unclear precisely how Bak and Bax promote outer mitochondrial membrane (OMM) permeabilisation. We suggest that Bax and Bak may not operate in precisely the same manner and evaluate the current models for their function. We also consider the emerging information that lipid-protein interactions may be crucial to the actions of Bax and Bak.
Insights
The pro-apoptotic proteins Bax and Bak are essential for releasing cytochrome c from mitochondria. Their precise mechanisms for outer mitochondrial membrane permeabilization are still being investigated, with lipid interactions playing a key role.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Bax and Bak, key Bcl-2 family proteins, are required for releasing apoptogens like cytochrome c from mitochondria.
- BH-3 only proteins, such as Bid, interact with Bcl-2 proteins to induce cell death.
- The exact mechanism by which Bax and Bak permeabilize the outer mitochondrial membrane (OMM) remains unclear.
Purpose of the Study:
- To evaluate current models of Bax and Bak function in OMM permeabilization.
- To explore the potential differences in how Bax and Bak promote OMM permeabilization.
- To consider the role of lipid-protein interactions in Bax and Bak activity.
Main Methods:
- Analysis of studies on Bax/Bak-deficient mouse cells.
- Review of existing models for Bax and Bak function.
- Consideration of emerging data on lipid-protein interactions.
Main Results:
- Bax and Bak are necessary for cytochrome c release from mitochondria.
- BH-3 only proteins mediate interactions at the mitochondrial surface.
- The precise mechanisms of OMM permeabilization by Bax and Bak are not fully elucidated.
- Emerging evidence suggests crucial roles for lipid-protein interactions.
Conclusions:
- Bax and Bak may function distinctly in promoting OMM permeabilization.
- Further research is needed to clarify the roles of Bax, Bak, and lipid-protein interactions in apoptosis.