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

线粒体是细胞的一部分，其中产生绝大多数细胞能量。 从细菌的运动到哺乳动物的心跳，每一种生物体的功能都需要这种能量。 在哺乳动物细胞中，当压力存在时，线粒体变得功能失调，能量的产生失调，最终细胞可能死亡。 虽然这一系列的有害影响是众所周知的，但在哺乳动物中，驱动线粒体功能障碍并最终在压力条件下失败的确切机制尚未完全了解。 无机聚磷酸盐（polyP）在这些机制中可能起重要作用。 PolyP具有类似于ATP的结构，ATP是细胞能量的主要分子。 多项研究表明，线粒体含有大量的聚P，并且这种化合物调节产生ATP的主要线粒体过程。 该项目将进行实验，以更好地了解正常条件和压力下polyP对线粒体的调节作用，以及这些作用的分子机制。 这些发现将进一步了解许多植物和动物的线粒体健康和能量产生受损的情况。 此外，该项目将使用多种方法来增加培训和扩大研究队伍，包括为该地区资源不足社区的本科生提供在我们实验室进行有偿研究的机会。压力诱导的线粒体功能障碍，包括失调的生物能量学，已被广泛描述在所有真核生物，它已被调查。 然而，在应激条件下驱动哺乳动物线粒体功能障碍并最终失败的机制尚未完全理解。 无机聚磷酸盐（polyP）是一种进化上保守的聚合物，存在于每种研究生物的每种组织中。 它是由正磷酸盐链通过高能磷酸酐键连接在一起形成的，类似于ATP中发现的那些。 这种分子结构，沿着其在哺乳动物线粒体中的高浓度，使得聚P成为有助于调节哺乳动物生物能量学的完美候选物。 事实上，许多研究人员已经证明了polyP在线粒体和线粒体外水平的能量产生中的调节作用。然而，在生物能量学中聚P的这种调节作用的确切分子机制仍然知之甚少。 在这里，将探索这些机制，使用野生型哺乳动物细胞和细胞酶促耗尽的线粒体聚P（MitoPPX）。 这些细胞将在对照和强制降解条件下使用。具体地说，应激将通过抗氧化系统的失调来诱导。 该研究项目的长期目标是增加线粒体生物学的知识，并有助于扩大研究人员的参与。 这将是通过纳入本科生从资源不足的社区在该地区的这项研究，以及通过提供这些学生有机会共同撰写的科学审查毕业前完成。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.