Novel mitochondria-to-lysosome crosstalk contributes to lysosomal dysfunction during aging

新型线粒体与溶酶体串扰导致衰老过程中溶酶体功能障碍

• 批准号: 10723050
• 负责人: Julie Kay Andersen
• 金额: $ 48.5万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723050
• 关键词: ATP Synthesis Pathway; Address; Affect; Age; Aging; Animals; Biological Models; Caenorhabditis elegans; Caloric Restriction; Cell Aging; Cell division; Cells; Charge; Communication; Cytosol; Defect; Deterioration; Disease; Electron Transport; Functional disorder; Future; Grant; Heterogeneity; Human; Image; Impairment; Individual; Inner mitochondrial membrane; Laboratories; Link; Longevity; Lysosomes; Mass Spectrum Analysis; Matrix Metalloproteinases; Membrane; Membrane Potentials; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Nematoda; Organelles; Organism; Phosphorylation; Play; Process; Proteins; Proton Pump; Protons; Provider; Rejuvenation; Reporting; Role; Sirolimus; Site; Source; Techniques; Testing; Therapeutic; Thinking; Time; Tissues; Vacuole; Work; Yeasts; age related; cell age; daughter cell; dietary restriction; experimental study; healthspan; improved; in vivo; in vivo Model; interest; mitochondrial dysfunction; mitochondrial membrane; model organism; new therapeutic target; novel; preservation; protein aggregation; proteostasis; segregation; senescence; sensor; therapeutic target; therapy development; vacuolar H+-ATPase

PROJECT SUMMARY/ABSTRACT Aging is accompanied by the gradual deterioration within each individual cellular compartments/organelles as well as the collapse of the interconnections among them, leading to the establishment of different hallmarks of aging. However, these hallmarks of aging, including loss of proteostasis, mitochondrial dysfunction, and cellular senescence, are traditionally studied separately and leave the connections among these hallmarks largely un- known. With a growing understanding of these inter-organelle interactions within young cells, it has become of interest to explore how losses in compartmental crosstalk contribute to the age-associated degeneration of or- ganelle function and the establishment/connection of hallmarks of aging. We recently discovered an unexpected crosstalk between mitochondria and the lysosome (vacuole in yeast) that explains age-associated vacuole/lysosome de-acidification, a process conserved from yeast to human cells and which contributes to the loss of proteostasis during aging and in many age-related diseases. We found that mitochondria contribute to the acidification of lysosome/vacuole via membrane contact sites. Moreover, our pre- liminary studies suggest that the collapse of mitochondria-vacuole contact during the replicative aging of yeast causes age-dependent de-acidification of vacuole. Similarly, we observed a close correlation between mitochon- dria and lysosome acidification in cultured human cells and in C. elegans, suggesting evolutionary conservation of this process. To address how aging affects the mitochondria-lysosome/vacuole contact and whether this mi- tochondria-to-lysosome axis plays a critical role in lysosome acidification in cellular senescence and animals, we here propose to investigate the mitochondria-lysosome/vacuole contact and lysosome/vacuole acidification dur- ing aging and in different longevity paradigms. Specifically, we will combine the expertise of our different model systems to (1) dissect the mechanism(s) underlying the age-related loss of mitochondria-vacuole connection in yeast; (2) determine mitochondrial contribution to lysosome acidification in human cells; and (3) dissect the roles of mitochondria-lysosome connection in lysosome acidification in C. elegans. Our studies will investigate a novel, possibly evolutionarily conserved inter-organelle communication connect- ing mitochondrial dysfunction and lysosome/vacuole de-acidification across different organisms and longevity paradigms. Although traditional thinking has held that age-associated lysosome/vacuole dysfunction is respon- sible for inducing mitochondrial dysfunction in a uni-directional manner, our study will determine whether mito- chondrial dysfunction may conversely impact on lysosome/vacuole dysfunction during aging revealing a here- to-fore unappreciated two-way crosstalk between these tightly connected organelles which may together con- tribute to several important hallmarks of aging. As such, the long-term implications of this study could be the identification of novel conserved therapeutic targets for age-related diseases with lysosome defects.

项目概要/摘要 衰老伴随着每个细胞区室/细胞器的逐渐退化，如 以及它们之间相互联系的崩溃，导致不同特征的建立 老化。然而，这些衰老的标志，包括蛋白质稳态丧失、线粒体功能障碍和细胞功能障碍， 衰老，传统上是分开研究的，并且这些特征之间的联系在很大程度上是不明确的。 已知。随着对年轻细胞内这些细胞器间相互作用的日益了解，它已成为 有兴趣探索区室串扰的损失如何导致与年龄相关的或- ganelle 功能和衰老标志的建立/联系。 我们最近发现线粒体和溶酶体（酵母中的液泡）之间存在意想不到的串扰 这解释了与年龄相关的液泡/溶酶体脱酸作用，这是从酵母到人类细胞保守的过程 这会导致衰老过程中以及许多与年龄相关的疾病中蛋白质稳态的丧失。我们发现 线粒体通过膜接触位点促进溶酶体/液泡的酸化。此外，我们的预 初步研究表明，酵母复制老化过程中线粒体-液泡接触的崩溃 导致液泡的年龄依赖性脱酸。同样，我们观察到线粒体之间存在密切的相关性。 培养的人类细胞和线虫中的干细胞和溶酶体酸化，表明进化保守 这个过程的。为了解决衰老如何影响线粒体-溶酶体/液泡接触以及这种情况是否 线粒体到溶酶体轴在细胞衰老和动物的溶酶体酸化中起着至关重要的作用，我们 这里建议研究线粒体-溶酶体/液泡接触和溶酶体/液泡酸化过程 衰老和不同的长寿范式。具体来说，我们将结合不同模型的专业知识 系统（1）剖析与年龄相关的线粒体-液泡连接丧失的潜在机制 酵母; (2) 确定线粒体对人体细胞溶酶体酸化的贡献； (3) 剖析角色 线虫溶酶体酸化中线粒体-溶酶体连接的研究。 我们的研究将调查一种新颖的、可能进化上保守的细胞器间通讯连接 不同生物体的线粒体功能障碍和溶酶体/液泡脱酸和寿命 范式。尽管传统观点认为年龄相关的溶酶体/液泡功能障碍是导致 可能以单向方式诱导线粒体功能障碍，我们的研究将确定线粒体是否 软骨功能障碍可能会反过来影响衰老过程中的溶酶体/液泡功能障碍，揭示了这一点- 迄今为止，这些紧密相连的细胞器之间存在未被意识到的双向串扰，这些串扰可能共同作用 致敬衰老的几个重要特征。因此，这项研究的长期影响可能是 鉴定具有溶酶体缺陷的年龄相关疾病的新保守治疗靶点。