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

• 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
• 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' 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

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.

该应用程序协同两个小组的专业知识，一个专门从事线粒体生物学， 蛋白质抑制信号传导和其他在V-ATP酶生物化学和液泡/溶酶体生物学。线粒体 是多功能的细胞器。线粒体除了在ATP生成中起主要作用外， 在其他细胞过程中，包括应激信号和细胞死亡。然而，在许多病理生理学 条件和老化期间，在何种程度上损害非生物能线粒体功能的贡献 对细胞适应性下降的影响知之甚少。我们发现各种线粒体应激源可以直接 通过一种名为 线粒体前体过度积累应激（mPOS）。mPOS影响细胞的机制 功能和可行性至今仍不清楚。溶酶体（或酵母中的液泡）也进行许多细胞内的 在细胞中的功能，包括pH控制，离子和氨基酸稳态，蛋白质降解，自噬和 囊泡运输有趣的是，线粒体和溶酶体功能的缺陷都有助于细胞凋亡。 衰老和与衰老相关的退行性疾病，包括帕金森病和肌萎缩侧索硬化症， 硬化症这种奇怪的巧合引发了一个问题，即线粒体和溶酶体的损伤是否可以 协同作用，无论是顺序或相加，以影响一个共同的细胞过程的健身和关键 老化细胞的存活。为了解决这个问题，重要的是要全面描述线粒体如何 和溶酶体在分子水平上相互作用以影响细胞功能。在这个应用程序中，我们专注于 一种新的线粒体-溶酶体应激信号通路，其中线粒体缺陷引起蛋白质抑制 应激到液泡/溶酶体，从而影响细胞存活。这项申请的科学前提是基于 基于我们在酵母、培养的人类细胞和转基因小鼠研究中获得的有力的初步数据。更 具体而言，该提案的目标1将检验特定线粒体应激可导致 对酵母液泡的严重蛋白抑制损伤。酵母系统的遗传顺从性将使我们能够 发现抑制细胞到液泡压力信号的基因，并可能延长细胞的寿命。 在目标2中，我们将在培养的哺乳动物细胞中验证这种新的细胞-溶酶体应激信号通路， 细胞在目标3中，我们将检验线粒体应激引起溶酶体损伤并影响细胞凋亡的假设。 体内组织稳态，使用我们最近开发的独特小鼠模型。康贝特人将以 在有丝分裂后组织中，ESTA诱导的溶酶体损伤的机制。我们实验的成功 可能揭示了一种新的细胞死亡机制，涉及细胞对溶酶体的应激信号。的 这些结果最终可能有助于更好地理解许多与衰老相关的疾病， 线粒体和溶酶体缺陷。