Mitochondrial inorganic polyphosphate (polyP) as a key regulator of mammalian mitochondrial physiology

Mitochondria are the part of the cells where the vast majority of cell energy is produced. This energy is needed for every organismal function, from the movement of bacteria to the heartbeats of mammals. In mammalian cells, when stress is present, mitochondria become dysfunctional, the production of energy is dysregulated and, eventually, cells can die. While this chain of deleterious effects is well known, the exact mechanisms that drive mitochondria to dysfunction and, eventually, to fail under stress conditions are not yet fully understood in mammals. Inorganic polyphosphate (polyP) could play an important role in these mechanisms. PolyP has a structure which is similar to that of ATP, the main molecule of cellular energy. Multiple studies have shown that mitochondria contain large amounts of polyP and that this compound regulates the main mitochondrial process of producing ATP. This project will carry out experiments to better understand the regulatory effects of polyP on mitochondria in normal conditions and under stress, as well as the molecular mechanisms that underly these effects. These findings will further basic understanding of many plant and animal conditions where mitochondria health and generation of energy are impaired. In addition, this project will use multiple methods to increase training and to expand the research workforce, including providing undergraduate students from underresourced communities in the area with paid research opportunities in our laboratory. Stress-induced mitochondrial dysfunction, including dysregulated bioenergetics, has been broadly described in all eukaryotic organisms where it has been investigated. However, the mechanisms that drive mammalian mitochondria to dysfunction and eventual failure under stress conditions are not yet fully understood. Inorganic polyphosphate (polyP) is an evolutionarily well conserved polymer that is present in every tissue from every studied organism. It is formed by chains of orthophosphates that are linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This molecular structure, along with its high concentration in mammalian mitochondria, makes polyP a perfect candidate to contribute to the regulation of mammalian bioenergetics. In fact, multiple researchers have demonstrated a regulatory role for polyP in energy production at both the mitochondrial and extra-mitochondrial levels. However, the exact molecular mechanisms that underly this regulatory role of polyP in bioenergetics remain poorly known. Here, these mechanisms will be explored, using both wild-type mammalian cells and cells enzymatically depleted of mitochondrial polyP (MitoPPX). These cells will be used under both control and stress conditions. Specifically, stress will be induced by dysregulating the antioxidant system. The long-term goal of this research project is to increase knowledge of mitochondrial biology, as well as to contribute to broadening participation of the research workforce. This will be accomplished through inclusion of undergraduate students from underresourced communities in the area in this research, as well as by providing these students with the opportunity to co-author a scientific review before graduation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.