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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：
9764361
负责人：
Andrew G Dillin
金额：
$ 34.39万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764361
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 fitness gain of function histone demethylase 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性神经退行性疾病的主要后果。