Inorganic polyphosphate as a chaperone in aging and in neurodegenerative diseases

无机聚磷酸盐作为线粒体伴侣在衰老中的作用。 线粒体功能障碍在衰老和阿尔茨海默氏症等神经退行性疾病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自身平衡系统和 随之而来的错误折叠的蛋白质在线粒体内的积累。这种蛋白质的动态平衡被触发 通过pH变化、热休克，特别是通过增加活性氧物种(ROS)。考虑到这一正常情况 线粒体功能是ROS产生的主要贡献者，ROS的积累要高得多 线粒体中的浓度高于其他亚细胞间的浓度。为了避免这种动态平衡失调，生物体 已经形成了主要由伴侣和蛋白酶介导的未折叠蛋白反应(UPR)。不饱和聚酯树脂 在内质网(ER)中，(UPRER)已被广泛研究。相比之下，规则和功能 对于线粒体的UPR，(UPRmt)仍然知之甚少，特别是在哺乳动物中。我们目前的知识 关于伴侣和蛋白水解酶不能解释保护幼体和幼体线粒体的强大系统 来自这种亚细胞环境中蛋白质错误折叠的高比率的健康生物在老化和 神经退行性变。这表明另一种强大的机制维持蛋白质的动态平衡。 在线粒体中。近年来，无机聚磷酸盐(Polyp)是一种在不同物种中保存良好的分子。 被描述为一种原始聚合物，在细菌以及其他细菌中具有普遍的伴侣作用 生物体，包括哺乳动物。我们假设息肉是线粒体蛋白的组成部分。 动态平衡。这项提议旨在确定息肉作为哺乳动物伴侣的重要性。 线粒体，抑制蛋白质动态平衡，维持线粒体的正确平衡 动力学和有丝分裂，以及线粒体中适当的生物能量学地位。因此，调制 息肉可以抵消衰老和神经退化中观察到的一些线粒体缺陷。在 在拟议的研究中，我们将把生物物理、生化和成像方法的使用与 使用具有不同水平的息肉的系统，以及错误折叠的蛋白质和 线粒体功能障碍是存在的。感谢一群杰出而知识渊博的导师、顾问 和合作者，K99/R00职业生涯独立道路的指导阶段将为我提供 我需要进行深入研究的衰老、动物工作、神经科学和蛋白质动态平衡方面的专业知识 线粒体蛋白质错误折叠的原因。这次培训将完成我在线粒体生物学方面的广泛背景， 细胞成像和药理学，这肯定会促进我向独立的过渡。人物刻画 对线粒体蛋白质稳态的创新质量控制途径将有助于解开这一机制 线粒体功能障碍在衰老和神经退变中的研究，为新的治疗方法铺平了道路 在这些情况下。

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.