Mitochondrial Permeability Transition
Normal mitochondria (left panel) use membrane potential to generate ATP. Permeability Transition (mPT) of the inner membrane causes its depolarization (right panel) and disrupts ATP production. mPT can occur through multiple molecular pathways specific to the disease type.
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. We are interested in understanding of the molecular mechanisms that cause mPT.
Biological functions of inorganic polyphosphate (polyP) in mammalian organisms
Inorganic polyphosphate (polyP) is a highly charged anionic polymer made from as few as ten to as many as several hundred phosphate molecules linked by phosphoanhydride bonds similar to that in ATP. Despite the ubiquitous presence of polyP in mammalian cells and the high concentrations of this polymer in mitochondria, very little is known about its function. Initially, my interest in polyP was focused on the investigation of its role as a putative component of the mPT. While working on this project, I realized that the unique physical-chemical properties and ubiquitous presence in cells polyP could support a central role of this polymer in a wide array of cellular functions. As a result of my collaborations with several internationally recognized research groups, over the past 15 years, we have developed a broad research program that is establishing how polyP regulates the function of mammalian cells. My group is also actively involved in the development of new analytical tools that will allow the role of polyP to be further elucidated in many types of mammalian cells. Over the past five years, my lab contributed two new research manuscripts that investigate the role of polyP in mitochondrial calcium signaling. In 2016 I also co-edited a book titled: “Inorganic Polyphosphates in Eukaryotic Cells”. This book is a 14 Chater’s collection of reviews of current leaders in the field.