Molecular mechanisms of signal transduction by the mitochondrial life-span regulators p66Shc and Sirtuins

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Several proteins have been identified which are involved in cellular aging processes and related diseases, including Sirtuin proteins and p66Shc. They are part of a complex signaling network synchronizing processes such as metabolic adaptation and apoptosis.Mammals have several isoforms of the NAD+-dependent protein deacetylases of the Sirtuin family. Three mitochondrial isoenzymes appear to contribute to regulation of energy metabolism and stress response. Similarly, the mitochondrial Shc isoform p66Shc acts as stress sensor and apoptosis regulator. Most molecular details of these signaling systems and their connections remain to be identified and might reveal attractive intervention points for therapy of aging-related diseases. We aim to identify and study in molecular detail the protein/protein interactions of the mitochondrial signaling proteins p66Shc, Sirt3, and Sirt5, which contribute to their localization, regulation, and substrate recognition. Interactions will be detected through affinity experiments, and substrates and regulators characterized in activity assays. Crystal structures of complexes with peptides, proteins, and small molecules will be solved. The interactions will be analyzed by site-directed mutagenesis, and we will attempt to exploit this information for the development of specific modulators.