MITOCHONDRIAL CALCIUM SIGNALLING AND APOPTOSIS: MOLECULAR DETERMINANTS AND REGULATORY MECHANISMS

The proposed research investigates cell death by apoptosis, the process that allows an organism to eliminate cells in excess (e.g. during organ development) or damaged (e.g. by pathogens or neoplastic transformation). In various genetic diseases, apoptosis is inappropriately triggered and leads to the degeneration of vital tissues. Mitochondria, the energy powerhouse of the cell, have also the important role of activating apoptosis at the appropriate time. When appropriate stimuli reach mitochondria, they change shape and release into the cell body proteins that activate apoptosis, thus triggering cell suicide. A critical signal reaching mitochondria is calcium. In response to a large number of external stimuli, Ca2+ flows into the cell, and reaches mitochondria. Amplitude and timing of the Ca2+ flux (a sort of “Ca2+ signature”) determines an effect that can range from a number of cell activities (contraction, secretion, etc.) to its death. In this project, we try to clarify how Ca2+ fluxes in mitochondria are regulated: which proteins transport Ca2+, and how different Ca2+ signals are produced in normal and diseased conditions. Understanding the mechanisms through which “death signals” are interpreted and identifying the proteins involved (new drug targets) could make it possible to develop innovative treatments of degenerative diseases. Finally, the project will study a specific genetic disease, myotonic dystrophy, as very interesting preliminary experiments have shown that the protein encoded by the affected gene changes the structure of mitochondria and causes cell death by apoptosis.