Mechanism and importance of mitochondrial import of BH3-only proteins during apoptosis

• Applicant: Professor Dr. Georg Häcker
• Subject Area: Cell Biology
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 63014790

The release of cytochrome c from a cell’s mitochondria is a key step in mitochondrial apoptosis. Although it is clear that the members of the Bcl-2 protein family regulate cytochrome c-release, it is still under dispute how this is achieved. Two models are presently discussed in the literature; both agree that the BH3-only group of Bcl-2 family proteins trigger the release, which then depends on the BH3-only protein dependent activation of the Bcl-2 family proteins Bax and Bak. However, the models are in almost complete disagreement as to the molecular occurrences. We have recently found that mitochondrial import/insertion of the BH3-only protein BimS into the outer mitochondrial membrane is essential for its pro-apoptotic function in yeast and mammalian models of mitochondrial apoptosis. In this project, we aim at understanding the molecular details and the general importance of mitochondrial import of BH3-only proteins for apoptosis. Mitochondrial insertion of the known BH3-only proteins and requirement of the mitochondrial import machinery will be tested. The question whether the activation of Bax and Bak relies on BH3-only protein import to the same degree will be analysed. The hypothesis will further be tested that mitochondrial insertion of BH3-only proteins is the trigger of mitochondrial translocation and thus activation of Bax. Finally, mitochondrial insertion of BH3-only proteins in cells undergoing apoptosis will be investigated.

• DFG Programme: Research Grants
• Participating Person: Dr. Stefan A. Paschen