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

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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.