A novel mitochondria-to-lysosome stress signaling pathway in degenerative disease and aging

退行性疾病和衰老中一种新的线粒体到溶酶体应激信号通路

基本信息

批准号：
10722759
负责人：
Xin Jie Chen
金额：
$ 40.75万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722759
关键词：
Address Affect Aging Alzheimer&apos s Disease Amino Acids Amyotrophic Lateral Sclerosis Atrophic Autophagocytosis Biochemistry Bioenergetics Biological Biology Carrier Proteins Cell Aging Cell Death Cell Death Induction Cell Membrane Permeability Cell Survival Cell physiology Cells Child Cytosol Data Defect Degenerative Disorder Development Dilated Cardiomyopathy Disease Energy Metabolism Environment Enzymes Facioscapulohumeral Muscular Dystrophy Frontotemporal Dementia Functional disorder Genes Genetic Goals Homeostasis Homologous Gene Human Impairment Ions Leigh Disease Longevity Lysosomes Mammalian Cell Mitochondria Mitochondrial Diseases Mitochondrial Proteins Modeling Molecular Multienzyme Complexes Multivesicular Body Mus Muscular Atrophy Mutation NADH dehydrogenase (ubiquinone)NAT2 gene Names Nuclear Organelles Oxidative Phosphorylation Parkinson Disease Pathogenicity Pathway interactions Phenotype Play Process Production Protein Import Proteins Proton Pump Rett Syndrome Role Signal Pathway Signal Transduction Skeletal Muscle Stress System Testing Tissues Transgenic Mice Vacuole Yeasts biochemical tools cell age detection of nutrient experimental study fitness frontotemporal lobar dementia amyotrophic lateral sclerosis gene discovery genomic tools in vivo late endosome mouse model novel overexpression postmitotic protein degradation stressor success synergism trafficking vacuolar H+-ATPase young adult

项目摘要

This application synergizes expertise from two groups, with one specialized in mitochondrial biology and proteostatic signaling and the other in V-ATPase biochemistry and vacuolar/lysosomal biology. Mitochondria are multifunctional organelles. In addition to their major role in ATP production, mitochondria are also involved in other cellular processes including stress signaling and cell death. However, under many pathophysiological conditions and during aging, to what extent impairment to non-bioenergetic mitochondrial functions contributes to the decline of cell fitness is poorly understood. We found that various mitochondrial stressors can directly induce proteostatic stress in the cytosol independent of energy metabolism, by a mechanism named mitochondrial Precursor Overaccumulation Stress (mPOS). The mechanisms by which mPOS affects cellular function and viability remain unknown so far. The lysosome (or vacuole in yeast) also carries out many cellular functions in the cell, including pH control, ion and amino acid homeostasis, protein degradation, autophagy and vesicular trafficking. Interestingly, defects in mitochondrial and lysosomal functions can both contribute to cell aging and aging-associated degenerative disorders, including Parkinson’s disease and amyotrophic lateral sclerosis. This odd coincidence invites the question of whether damage to mitochondria and lysosomes can synergize, either sequentially or additively, to affect a common cellular process critical for the fitness and survival of aged cells. To address this question, it is important to comprehensively describe how mitochondria and lysosomes interact at the molecular level to affect cellular functions. In this application, we focus on a novel mitochondria-to-lysosome stress signaling pathway, in which mitochondrial defects cause proteostatic stress to the vacuole/lysosome thereby affecting cell survival. The scientific premise of this application is based on our strong preliminary data from studies in yeast, cultured human cells and transgenic mice. More specifically, the Aim 1 of the proposal will test the hypothesis that specific mitochondrial stress can cause severe proteostatic damage to the yeast vacuole. The genetic amenability of the yeast system will enable us to discover genes that suppress the mitochondria-to-vacuole stress signaling and possibly, extend cell’s lifespan. In Aim 2, we will validate this novel mitochondria-to-lysosome stress signaling pathway in cultured mammalian cells. In Aim 3, we will test the hypothesis that mitochondrial stress causes lysosomal damage and affects tissue homeostasis in vivo, using a unique mouse model that we recently developed. We will determine the mechanism of the mitochondria-induced lysosomal damage in post-mitotic tissues. Success of our experiments may unravel a novel mechanism of cell demise that involves mitochondria-to-lysosome stress signaling. The results may ultimately help the better understanding of many aging-associated diseases that are co-manifested by mitochondrial and lysosomal defects.

该应用程序使两组的专业知识协同，其中一个专门从事线粒体生物学和蛋白质信号传导，另一个在V-ATPase生物化学和液泡/溶酶体生物学中。线粒体是多功能细胞器。除了它们在ATP生产中的主要作用外，线粒体还涉及在其他细胞过程中，包括应力信号传导和细胞死亡。但是，在许多病理生理学下条件和衰老期间，非生物能的线粒体功能在多大程度上损害了细胞健身的衰落知之甚少。我们发现各种线粒体应激源可以直接通过一种名为线粒体前体过度累积应力（MPO）。 MPO影响细胞的机制到目前为止，功能和生存能力仍然未知。溶酶体（或酵母中的吸尘器）也进行了许多细胞细胞的功能，包括pH控制，离子和氨基酸稳态，蛋白质降解，自噬和囊泡贩运。有趣的是，线粒体和溶酶体功能的缺陷都可以有助于细胞衰老和衰老相关的退化性疾病，包括帕金森氏病和肌萎缩症硬化。这种奇怪的巧合引起了一个问题，即对线粒体和溶酶体的损害是否可以顺序或另外，协同作用，影响适应性至关重要的常见蜂窝过程老化细胞的存活。要解决这个问题，重要的是要全面描述线粒体溶酶体在分子水平上相互作用以影响细胞功能。在此应用程序中，我们专注于新型的线粒体到散热体应力信号传导途径，其中线粒体缺陷引起蛋白质静脉对吸尘/溶酶体的压力，从而影响细胞存活。该应用程序的科学前提是基于关于我们从酵母，培养的人类细胞和转基因小鼠研究的强大初步数据。更多的具体而言，该提案的目标1将检验以下假设：特定的线粒体应力可能导致严重的蛋白质抑制酵母真空吸尘器。酵母系统的遗传性不适，将使我们能够发现抑制线粒体到磁管应力信号的基因，并可能延长细胞的寿命。在AIM 2中，我们将验证这种新颖的线粒体到散热体应力信号传导途径细胞。在AIM 3中，我们将检验以下假设：线粒体应激会导致溶酶体损伤并影响组织体内稳态在体内使用我们最近开发的独特小鼠模型。我们将确定线粒体诱导的溶酶体损伤的机理。实验的成功可能会揭开细胞衰减的新机制，涉及线粒体到散糖体应力信号传导。这结果最终可能有助于更好地理解与同事相关的许多相关疾病线粒体和溶酶体缺陷。