Molecular mechanisms of the mitochondrial permeability transition

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The overarching goal of my research program is to identify and characterize molecular mechanisms responsible for stress-induced permeabilization of the mitochondrial inner membrane. In most eukaryotic cells, mitochondria are the primary source of the energy that they provide in the form of ATP by performing oxidative phosphorylation (OXPHOS). OXPHOS is a two-step process. First, substrate oxidation by the respiratory chain results in the generation of the electrical potential on the mitochondrial inner membrane. This potential energy drives generation of ATP by the phosphorylation of ADP at the ATP synthase complex. To prevent energy dissipation and ensure that OXPHOS is efficient mitochondrial inner membrane permeability should be tightly controlled and maintained at low levels. Stress conditions associated with dysregulation of calcium and ROS homeostasis can lead to an increase in mitochondrial inner membrane permeability – a phenomenon known as Mitochondrial Permeability Transition (mPT). mPT causes dissipation of the membrane potential and loss of mitochondrial ATP-generating capacity leading to cell dysfunction and death. mPT is critically involved in a broad spectrum of diseases ranging from heart attack to neurodegeneration. Prevention of mPT is highly protective against cell death and tissue damage suggesting high therapeutics potential. However, molecular mechanisms of mPT are not well understood, and this gap in knowledge prevents mPT from being a drug target. Over the past five years, we demonstrated that mPT is a multifaceted phenomenon and depending on the disease type and stress severity, it can occur through different pathways. The central goal of our research program is to identify the link between specific molecular mechanisms of mPT and specific stress conditions. We have already established several original animal and cell disease-relevant models causing different types of mPT. In our approach, a variety of methods that measure the mPT and tissue damage at the organismal, cellular and mitochondrial levels are coupled with a number of our original electrophysiological (patch- clamp) assays that allow direct measurement of mPT at the level of mitochondrial membranes and give us a unique opportunity to dissect and characterize its multiple identities and regulation. The results of our study will provide a detailed understanding of one of the most critical events in cell death cascades and will bring an essential framework for the development of therapeutically approaches that will selectively target mPT.