The interaction of Cofilin and mitochondria

The Erwin Schrödinger research project The interaction of Cofilin and mitochondria aims at the molecular characterisation of the Cofilin-mitochondria interaction. Cofilin is a small protein regulating the dynamic remodelling of the actin cytoskeleton, which essentially shapes all living cells. Cofilin still remains uncharacterised in some of its functions. Recent publications strongly suggest an interaction of Cofilin with mitochondria under conditions of stress. This interaction is likely to have an impact on the regulation of cell death, because mitochondria are central to the signalling processes of the intrinsic cell death pathway. However, a physical interaction of Cofilin and mitochondria has not been reported to date. Since the interaction is likely to be crucial for cell death signalling, our proposal directly aims to close this gap in our current knowledge. Importantly, the regulation of cell death, especially the intrinsic mitochondria dependent pathway, is of high relevancefor human neurodegenerative diseases such as Alzheimers and Parkinsons, but also cancer. Therefore, the proposed research project is likely to reveal new targets for disease treatment. To determine whether the Cofilin/ mitochondria interaction is a physical one, we will employ live cell microscopy, sophisticated yeast genetics and biochemistry methods, using yeast cells and mammalian cell lines. To investigate the molecular interaction on a structural level we will apply state of the art nuclear magnetic resonance (NMR) technology. Thus, the proposed research project will reveal novel physical interactions at high resolution and mechanistic insight in stress- and cell death signalling, with major importance for neurodegenerative disease and cancer research.

The Erwin Schrödinger project The interaction of Cofilin and Mitochondria aimed at investigating whether and how the actin-regulating protein cofilin can participate in the communication with mitochondria. Our experiments indeed delivered significant evidence for cofilins involvement in a cellular stress response pathway which depends on a mitochondrial outer membrane protein. In all eukaryotic organisms the actin cytoskeleton is critical for the determination of cell architecture. It is structurally dynamic and its remodelling is regulated by small actin binding proteins such as cofilin. Despite its crucial role in actin remodelling, Cofilin still remains uncharacterised in some of its functions. Our study delivers evidence that cofilin controls a cellular stress response pathway which depends on a mitochondrial outer membrane protein. The use of a yeast cofilin mutant library allowed us to develop a detailed picture of this stress response pathway. We obtained similar results with an alternative approach involving pharmacological manipulation of the actin cytoskeleton. Interestingly, we also revealed that the induced stress response largely depends on lipid metabolism. We could further show that the stress response regulates cell death and thus has an impact on yeast ageing. Importantly, the regulation of cell death is of high relevance for human diseases and ageing. These include neurodegenerative diseases such as Alzheimers and Parkinsons, but also cancer. Therefore, our so far unpublished research results are likely to reveal new targets for disease treatment in the future.