Inorganic polyphosphate as a chaperone in aging and in neurodegenerative diseases

无机多磷酸盐作为衰老过程中的线粒体伴侣。 线粒体功能障碍在衰老和神经退行性疾病（如阿尔茨海默氏症）中起着至关重要的作用 疾病这种功能障碍的主要原因之一是蛋白质稳态系统的损害， 线粒体内错误折叠的蛋白质随之积累。这种蛋白质稳态失调被触发 通过pH改变，热休克，特别是通过增加活性氧（ROS）。鉴于正常 线粒体功能是ROS产生的主要贡献者，ROS积累到高得多的水平， 线粒体中的浓度比其他亚细胞区室中的浓度高。为了避免这种平衡失调， 已经开发出主要由分子伴侣和蛋白酶介导的未折叠蛋白反应（UPR）。UPR 在内质网（ER），（UPRER）已被广泛研究。与此相反， 线粒体不饱和蛋白酶（UPRmt），仍然知之甚少，特别是在哺乳动物中。我们目前的知识 关于伴侣蛋白和蛋白酶的研究不能解释保护年轻人线粒体的强大系统， 健康的生物体在衰老过程中存在于这种亚细胞环境中的蛋白质错误折叠的高比率， 神经变性这表明有另一种强大的机制维持着蛋白质的稳态 在线粒体中。近年来，无机聚磷酸盐（polyP），这是一个非常保守的分子之间的不同 物种，被描述为一种原始聚合物，在细菌中具有普遍的伴侣作用，以及在其他 生物，包括哺乳动物。我们假设polyP是线粒体蛋白质的一个组成部分， 体内平衡该建议旨在确定聚P作为哺乳动物伴侣蛋白的重要性。 线粒体，抑制蛋白质稳态失调，维持线粒体的正确平衡 动力学和线粒体自噬，以及线粒体中适当的生物能量学状态。因此，调制 polyP可以抵消衰老和神经退行性变中观察到的一些线粒体缺陷。在 建议的研究，我们将耦合使用生物物理，生物化学和成像为基础的方法， 使用具有不同水平polyP的系统，以及错误折叠蛋白质和 存在线粒体功能障碍。感谢一群杰出而知识渊博的导师、顾问 和合作者，K99/R 00职业独立之路的指导阶段将为我提供 在衰老、动物研究、神经科学和蛋白质稳态方面的专业知识， 线粒体蛋白质错误折叠这次培训将完善我在线粒体生物学方面的广泛背景， 细胞成像和药理学，肯定会促进我向独立的过渡。表征 线粒体蛋白质稳态的创新质量控制途径将有助于解开机制 衰老和神经退行性变中线粒体功能障碍的研究，为新的治疗方法铺平了道路 对于这些条件。

INORGANIC POLYPHOSPHATE AS A MITOCHONDRIAL CHAPERONE IN AGING. Mitochondrial dysfunction plays a crucial role in aging and in neurodegenerative diseases, such as Alzheimer’s disease. One of the main contributors to this dysfunction is impairment of the protein homeostasis systems and the consequent accumulation of misfolded proteins within mitochondria. This protein dyshomeostasis is triggered by pH alterations, heat shock and, especially, by increased reactive oxygen species (ROS). Given that normal mitochondrial function is the main contributor to ROS generation, ROS accumulate to much higher concentrations in mitochondria than in other subcellular compartments. To avoid this dyshomeostasis, organisms have developed the unfolded protein response (UPR), mediated primarily by chaperones and proteases. UPR in the endoplasmic reticulum (ER), (UPRER) has been studied extensively. In contrast, the regulation and function of the mitochondrial UPR, (UPRmt), remains poorly understood, especially in mammals. Our current knowledge about chaperones and proteases cannot explain the robust system that protects mitochondria in young and healthy organisms from the high rates of protein misfolding present in this subcellular environment in aging and neurodegeneration. This suggests that an alternative and powerful mechanism maintains protein homeostasis in mitochondria. Recently, inorganic polyphosphate (polyP), which is a well-conserved molecule among different species, was described as a primordial polymer with a universal chaperone role in bacteria, as well as in other organisms, including mammals. We hypothesize that polyP is an integral component of mitochondrial protein homeostasis. This proposal aims to determine the importance of polyP as a chaperone in mammalian mitochondria, suppressing protein dyshomeostasis and maintaining the correct balance of mitochondrial dynamics and mitophagy, as well as the appropriate bioenergetics status in mitochondria. Thus, the modulation of polyP could counteract some of the mitochondrial defects observed in aging and neurodegeneration. In the proposed studies, we will couple the use of biophysical, biochemical and imaging-based approaches with the use of systems with different levels of polyP, as well as cellular models where misfolded proteins and mitochondrial dysfunctions are present. Thanks to an outstanding and knowledgeable group of mentors, advisors and collaborators, the mentored phase of the K99/R00 Career Pathway to Independence will provide me with the expertise in aging, animal work, neurosciences and protein homeostasis that I need to conduct a deep study of mitochondrial protein misfolding. This training will complete my extensive background in mitochondrial biology, cell imaging and pharmacology, and will definitely facilitate my transition to independence. The characterization of an innovative quality control pathway on mitochondrial protein homeostasis will help to unravel the mechanism of mitochondrial dysfunctions in aging and neurodegeneration, paving the road to new therapeutic approaches for these conditions.