Inorganic polyphosphate as a chaperone in aging and in neurodegenerative diseases

无机多磷酸盐作为衰老和神经退行性疾病的伴侣

基本信息

批准号：
10210342
负责人：
Maria de la Encarnacion Solesio Torregrosa
金额：
$ 23.97万
依托单位：
RUTGERS THE STATE UNIV OF NJ CAMDEN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210342
关键词：
Address Affect Affinity Aging Alzheimer&apos s Disease Animals Apoptosis Apoptotic Bacteria Biochemical Bioenergetics Biology Biophysics Career Choice Cell Aging Cell Death Cell Fractionation Cell Line Cell model Cells Cyclic AMP Data Defect Dipyridamole Endoplasmic Reticulum Environment Enzyme-Linked Immunosorbent Assay Equilibrium Functional disorder Gel Generations Genus Hippocampus Goals Heat-Shock Response Human Impairment Knowledge Length Mammalian Cell Mammals Mediating Mentors Metabolism Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Chaperones Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Neurosciences OPA1 gene Organism PINK1 gene Pathology Pathway interactions Peptide Hydrolases Pharmacology Phase Plasmids Play Polymers Polyphosphates Polyps Process Proteins Quality Control Reactive Oxygen Species Regulation Role Sepharose Stimulus Stress System Technology Testing Training Western Blotting Work age related neurodegeneration amyloid peptide analog cellular imaging cytotoxicity imaging approach immunocytochemistry inhibitor/antagonist innovation metabolic abnormality assessment misfolded protein mitochondrial dysfunction mitochondrial membrane mitochondrial metabolism novel therapeutic intervention phosphoric diester hydrolase prevent protective effect protein aggregation protein folding protein misfolding proteostasis response senescence stressor success tool

项目摘要

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.

无机多磷酸盐作为衰老中的线粒体伴侣。线粒体功能障碍在衰老和神经退行性疾病中起着至关重要的作用，例如阿尔茨海默氏症疾病。这种功能障碍的主要因素之一是蛋白质稳态系统的损害和随之而来的错误折叠蛋白在线粒体内的积累。该蛋白质dyshomeostasis触发通过pH的改变，热休克，尤其是通过增加的活性氧（ROS）。考虑到正常线粒体功能是ROS产生的主要贡献者，ROS积累到更高线粒体中的浓度比其他亚细胞隔室中的浓度。为了避免这种dyshomeostasis，有机体已经开发出未折叠的蛋白质反应（UPR），该反应是由伴侣和蛋白酶介导的。 UPR 在内质网（ER）中，（Uprer）已广泛研究。相反，调节和功能线粒体UPR（UPRMT）的理解仍然很差，尤其是在哺乳动物中。我们目前的知识关于伴侣和保护酶不能解释保护年轻线粒体和健康的生物体，来自这种亚细胞环境中在衰老和神经变性。这表明一种替代和强大的机制维持蛋白质稳态在线粒体中。最近，无机多磷酸盐（息肉），它是不同的分子。物种被描述为一种原始聚合物，在细菌中以及其他生物，包括哺乳动物。我们假设息肉是线粒体蛋白的组成部分稳态。该建议旨在确定息肉在哺乳动物中的伴侣的重要性线粒体，抑制蛋白质异质体并保持线粒体的正确平衡动力学和线粒体以及线粒体中适当的生物能状态。那，调制息肉可以抵消在衰老和神经变性中观察到的一些线粒体缺陷。在拟议的研究，我们将对基于生物物理，生化和基于成像的方法的使用与使用具有不同质量息肉的系统，以及错误折叠蛋白质和的细胞模型线粒体功能障碍存在。感谢一群杰出且知识渊博的导师，顾问和合作者，K99/R00职业途径的修改阶段将为我提供我需要进行深入研究线粒体蛋白的错误折叠。这项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，肯定会支持我向独立的过渡。表征线粒体蛋白稳态上的创新质量控制途径将有助于解开机制衰老和神经变性中的线粒体功能障碍，铺平了通往新治疗方法的道路对于这些条件。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inorganic Polyphosphate, Mitochondria, and Neurodegeneration.

无机多磷酸盐、线粒体和神经变性。

DOI：
10.1007/978-3-031-01237-2_3
发表时间：
2022
期刊：
Progress in molecular and subcellular biology
影响因子：
0
作者：
Urquiza,Pedro;Solesio,MariaE
通讯作者：
Solesio,MariaE

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function.

DOI：
10.3390/cells10061552
发表时间：
2021-06-19
期刊：
Cells
影响因子：
6
作者：
Guitart-Mampel M;Urquiza P;Borges JI;Lymperopoulos A;Solesio ME
通讯作者：
Solesio ME

Toolkit for cellular studies of mammalian mitochondrial inorganic polyphosphate.

DOI：
10.3389/fcell.2023.1302585
发表时间：
2023
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
通讯作者：

Mitochondrial Inorganic Polyphosphate (polyP) Is a Potent Regulator of Mammalian Bioenergetics in SH-SY5Y Cells: A Proteomics and Metabolomics Study.

DOI：
10.3389/fcell.2022.833127
发表时间：
2022
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Guitart-Mampel M;Urquiza P;Carnevale Neto F;Anderson JR;Hambardikar V;Scoma ER;Merrihew GE;Wang L;MacCoss MJ;Raftery D;Peffers MJ;Solesio ME
通讯作者：
Solesio ME

Enzymatic Depletion of Mitochondrial Inorganic Polyphosphate (polyP) Increases the Generation of Reactive Oxygen Species (ROS) and the Activity of the Pentose Phosphate Pathway (PPP) in Mammalian Cells.