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

线粒体无机多磷酸盐 (polyP) 作为哺乳动物线粒体生理学的关键调节剂

• 批准号: 2327684
• 负责人: Maria Solesio Torregrosa
• 金额: $ 95万
• 依托单位: Rutgers University Camden
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2327684&HistoricalAwards=false
• 关键词: Mitochondrial; inorganic; polyphosphate; polyP; key

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.

线粒体是细胞中产生绝大多数细胞能量的部分。从细菌的运动到哺乳动物的心跳，每一种生物体的活动都需要这种能量。在哺乳动物细胞中，当压力存在时，线粒体功能失调，能量的产生受到失调，最终细胞可能死亡。虽然这一连串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应激条件下失败的确切机制还不完全清楚。无机聚磷酸盐(Polyp)可能在这些机制中发挥重要作用。息肉的结构与细胞能量的主要分子三磷酸腺苷相似。多项研究表明，线粒体中含有大量的息肉，这种化合物调节着线粒体产生ATP的主要过程。该项目将进行实验，以更好地了解正常条件下和应激状态下息肉对线粒体的调节作用，以及这些作用的分子机制。这些发现将进一步加深对线粒体健康和能量产生受损的许多动植物疾病的基本了解。此外，该项目将使用多种方法来增加培训和扩大研究队伍，包括为来自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。应激诱导的线粒体功能障碍，包括调节失调的生物能量学，已经在所有研究它的真核生物中得到了广泛的描述。然而，在应激条件下，驱动哺乳动物线粒体功能障碍和最终失效的机制还没有完全被了解。无机聚磷酸盐(Polyp)是一种进化上保守的聚合物，存在于每个被研究生物体的每个组织中。它是由正磷酸链通过高能的磷酸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，加上它在哺乳动物线粒体中的高浓度，使息肉成为调节哺乳动物生物能量学的完美候选者。事实上，多位研究人员已经证明了息肉在线粒体和线粒体外水平上对能量产生的调节作用。然而，息肉在生物能量学中调节作用的确切分子机制仍然知之甚少。在这里，将使用野生型哺乳动物细胞和酶耗尽的线粒体息肉(MitoPPX)细胞来探索这些机制。这些细胞将在控制和应激条件下使用。具体地说，压力是由抗氧化系统失调引起的。这项研究项目的长期目标是增加线粒体生物学知识，并为扩大研究队伍的参与做出贡献。这将通过将该地区资源不足社区的本科生纳入这项研究，以及为这些学生提供在毕业前共同撰写一篇科学评论的机会来实现。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。