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Mitochondrial complex III-derived ROS in astrocytic signaling and Alzheimer's disease-related pathogenesis

线粒体复合物 III 衍生的 ROS 在星形胶质细胞信号传导和阿尔茨海默病相关发病机制中的作用

基本信息

批准号：
10749159
负责人：
Daniel Martin Barnett
金额：
$ 4.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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 2026-07-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Mitochondrial reactive oxygen species (ROS) are strongly implicated in the pathogenesis of diverse aging- associated neurological disorders, including Alzheimer's disease (AD) and frontotemporal dementia. Mitochondria produce ROS during oxidative metabolism and increased production of mitochondrial ROS are causally linked to various processes in AD, including aging, amyloid precursor protein/amyloid-β (APP/Aβ) pathology, tauopathy, and neuroinflammation. Recent work suggests that ROS produced by different mitochondrial sites have distinct roles in cell signaling and disease. However, previous tools to suppress mitochondrial ROS were not site-selective, disrupted respiration, or inhibited ROS only after release rather than blocking production. Thus, the roles of mitochondrial ROS in AD pathogenesis require investigation. Mitochondrial complex III has a large capacity for ROS production and generates ROS toward the cytosol, poising it to regulate intracellular signaling and disease mechanisms. To investigate the effects of complex III- derived ROS, our lab has identified and characterized small molecules that suppress complex III ROS production (S3QELs, “sequels”), but do not block ROS production by other mitochondrial sites or affect other mitochondrial processes. In our preliminary studies using S3QELs, we found that AD-associated neuroimmune factors enhance astrocytic complex III ROS and that complex III ROS promote JAK-STAT3 signaling and gene expression changes linked to disease. In astrocytic-neuronal cultures, S3QELs prevented neuronal dysfunction linked to tauopathy, but did not affect neurons cultured in isolation. In addition, S3QELs reduced neuroimmune and glial alterations in mice expressing mutant human tau. These data implicate complex III ROS in astrocytic signaling and AD-related cascades. I propose to test my central hypotheses that astrocytic complex III ROS are increased by specific disease-related stimuli and modulate astrocytic functions and dementia-linked pathogenic processes through oxidation of distinct cysteine targets, including those related to STAT3. In Aim 1, I will use a genetically-encoded ratiometric H2O2 sensor targeted to specific subcellular compartments in primary mouse and human iPSC-derived astrocytes to define the exact patterns and upstream triggers of astrocytic complex III ROS. I will also use genetic and pharmacological tools to determine the roles of complex III ROS in astrocytic signaling, gene expression, and astrocytic-neuronal interactions. In Aim 2, I will use innovative redox proteomics methods to broadly profile complex III ROS-mediated cysteine oxidation and use targeted and cell-specific genetic manipulations to assess how oxidation of specific cysteine sites alters astrocytic signaling and pathological cascades linked to dementia. The proposed study is likely to elucidate novel oxidative mechanisms that regulate glial signaling and disease cascades and could lead to the development of targeted and effective therapies for aging-related dementias.

项目总结/文摘