Investigation of the molecular composition and mechanisms of induction of the mitochondrial permeability transition pore

The prevention of excessive cell death is a key strategy during the treatment of heart attacks and strokes. In order for this treatment to be efficient, it is essential to identify, at the molecular level, those central events which occur during pathology and are responsible for cell death. It has been demonstrated that activation of the mitochondrial permeability transition pore (mPTP) is a major cause of cell death during heart attack and stroke. Furthermore, it is known that preventing pore activation is strongly protective, which makes it a very effective target for drug treatment. Determining the molecular composition of mPTP will be a major step towards the development of specific drugs to prevent its activation, and, ultimately, save patients' lives. At present, and in spite of 30 years of intensive research, the molecular composition of mPTP is not known. The main goal of current proposal is to answer the question of the molecular identity of mPTP. Specifically, we will investigate the possibility that mPTP is assembled of two polymers: polyphosphate and polyhydroxybutyrate. Furthermore, we will try to demonstrate that mPTP can be inhibited by decreasing the levels of these polymers in the cell. Overall, the completion of this study will make significant contributions to our understanding of the basic mechanisms of cell pathology and possibly present a strategy for its practical use in the treatment of disease.