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Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

线粒体应激信号传导和蛋白质稳态的神经内分泌协调

基本信息

批准号：
10192720
负责人：
Andrew G Dillin
金额：
$ 34.33万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192720
关键词：
Adult Affect Age of Onset Aging Animals Behavior Binding CXCR3 gene Caenorhabditis elegans Cell membrane Cells ChIP-seq Chromatin Complex Data Development Distal Endocytosis Enzymes Epigenetic Process Event Family Future Gene Expression Profile Generations Genes Genetic Transcription Goals Health Homeostasis Iron Life Longevity Mediating Mediator of activation protein Metabolic Metabolic stress Metabolism Mitochondria Modification Molecular Nature Nematoda Neurodegenerative Disorders Neurons Neurosecretory Systems Neurotransmitters Nutrient Organ Organism Pathway interactions Pattern Perception Play Process Production Proteins Recycling Reporting Role Sensory Series Serotonin Signal Pathway Signal Transduction Stress Time Tissues Up-Regulation WNT Signaling Pathway Work alpha ketoglutarate base biological adaptation to stress chromatin modification chromatin remodeling design experience experimental study gain of function histone demethylase metabolic fitness mitochondrial dysfunction mutant preservation promoter proteostasis receptor response survivorship transcription factor

项目摘要

Mitochondrial dysfunction is a primary consequence of nearly all age-onset neurodegenerative diseases. Across eukaryotic species, however, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Studies on the roles of mitochondria in the aging process have suggested that reduced mitochondrial function during a critical window of development in the nematode C. elegans is sufficient to extend the lifespan of the organism. Mitochondrial stress during this time results in a massive and persistent restructuring in gene expression patterns, as evidenced by analyses of long-lived mitochondrial mutant animals. This sustained response to an early metabolic stress may allow the organism to adapt its adult metabolism to match predicted states of nutrient availability. Previously, we reported that reduced mitochondrial function specifically in the neurons was sufficient to extend the lifespan of the nematode C. elegans. Mild neuronal mitochondrial stress also caused an upregulation in mitochondrial stress signaling across distal tissues of the organism. We now report evidence for the requirement of a class of metabolic neurotransmitters in the dissemination of perceived mitochondrial stress. We also observe a neuron-specific epigenetic remodeling in response to mitochondrial dysfunction. We hypothesize that, after sensing metabolic stress, neurons transcriptionally remodel their gene expression patterns by activating a class of neuron-specific chromatin modifying enzymes. Transcriptional changes in the neurons then initiate a downstream neuroendocrine signaling event that is capable of activating mitochondrial stress responsive pathways across tissues and organs. This cascade of responses collectively serves to increase the metabolic fitness and lifespan of the organism.

线粒体功能障碍是几乎所有年龄发病的神经退行性疾病的主要后果。然而，在真核物种中，轻微的线粒体应激可以对真核生物的寿命产生有益的影响。有机体。关于线粒体在衰老过程中的作用的研究表明，线粒体减少线虫线虫发育的关键窗口期间的线粒体功能足以延长有机体的寿命。这段时间的线粒体应激会导致大量且持续的基因表达模式的重组，如对长寿命线粒体突变体的分析所证明的那样动物。这种对早期代谢应激的持续反应可能使有机体适应其成年期新陈代谢以匹配营养可用性的预测状态。之前，我们报道了神经元中线粒体功能的减少足以延长线虫的寿命。 elegans。轻度神经元线粒体应激也导致跨越生物体远端组织的线粒体应激信号。我们现在报告证据在感知线粒体应激的传播中需要一类代谢神经递质。我们还观察到针对线粒体功能障碍的神经元特异性表观遗传重塑。我们假设，在感受到代谢压力后，神经元转录重塑其基因表达通过激活一类神经元特异性染色质修饰酶来改变模式。转录变化然后神经元启动下游神经内分泌信号事件，能够激活线粒体跨组织和器官的应激反应通路。这一系列反应共同作用是增加有机体的代谢适应性和寿命。