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.

项目摘要/摘要 衰老伴随着每个单独的细胞室/细胞器中的逐渐恶化 以及它们之间的互连崩溃，导致建立不同的标志 老化。然而，这些衰老的标志，包括蛋白抑制作用，线粒体功能障碍和细胞的丧失 传统上对衰老进行了分开研究，并在这些标志之间留下联系。 已知。随着对年轻细胞中这些轨道间相互作用的越来越多的了解，它已成为 兴趣探索隔室串扰中的损失如何促进与年龄相关的OR-的变性 Ganelle功能以及衰老标志的建立/联系。 最近，我们发现线粒体和溶酶体之间的意外串扰（酵母中的液泡） 这解释了与年龄相关的液泡/溶酶体去酸化，这是从酵母到人类细胞保守的过程 这有助于在衰老和许多与年龄相关的疾病中丧失蛋白质的衰老。我们发现 线粒体有助于通过膜接触部位溶酶体/液泡的酸化。而且，我们的预先 Limarinary研究表明，酵母复制衰老期间线粒体 - 维库尔接触的崩溃 导致液泡的年龄依赖性去酸化。同样，我们观察到了线条之间的密切相关性 培养的人类细胞和秀丽隐杆线虫中的DRIA和溶酶体酸化，表明进化保存 这个过程。解决衰老如何影响线粒体赖以溶质体/液泡接触以及该mi-是否存在 Tooncondria到散粒体轴在细胞衰老和动物中在溶酶体酸化中起关键作用，我们 这里建议研究线粒体 - 溶质体/液泡接触和溶酶体/液泡酸化 衰老和不同的寿命范式。具体来说，我们将结合不同模型的专业知识 （1）剖析与年龄相关的线粒体 - 维库尔连接损失的机制 酵母; （2）确定人类细胞中溶酶体酸化的线粒体贡献； （3）剖析角色 秀丽隐杆线虫中溶酶体酸化中的线粒体 - 溶酶体连接的。 我们的研究将研究一种新颖的，可能在进化上保守的轨道间通讯连接 - 跨不同生物和寿命的线粒体功能障碍和溶酶体/液泡去酸化 范式。尽管传统思想认为与年龄相关的溶酶体/液泡功能障碍是响应的 可用于以单向方式诱导线粒体功能障碍的11- 在衰老期间，软骨功能障碍可能对溶酶体/液泡功能障碍产生影响 因此，在这些紧密连接的细胞器之间未经欣赏的双向串扰，这可能会结合在一起 向衰老的几个重要标志致敬。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型保守治疗靶标。