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      Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

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          Abstract

          Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPR mt) and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPR mt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPR mt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPR mt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system.

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          Most cited references29

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          The impact of the unfolded protein response on human disease

          A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.
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            A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity.

            We report a systematic RNA interference (RNAi) screen of 5,690 Caenorhabditis elegans genes for gene inactivations that increase lifespan. We found that genes important for mitochondrial function stand out as a principal group of genes affecting C. elegans lifespan. A classical genetic screen identified a mutation in the mitochondrial leucyl-tRNA synthetase gene (lrs-2) that impaired mitochondrial function and was associated with longer-lifespan. The long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differential responses to free-radical and other stresses. These data suggest that the longer lifespan of C. elegans with compromised mitochrondria cannot simply be assigned to lower free radical production and suggest a more complex coupling of metabolism and longevity.
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              Inactivation of conserved C. elegans genes engages pathogen- and xenobiotic-associated defenses.

              The nematode C. elegans is attracted to nutritious bacteria and is repelled by pathogens and toxins. Here we show that RNAi and toxin-mediated disruption of core cellular activities, including translation, respiration, and protein turnover, stimulate behavioral avoidance of normally attractive bacteria. RNAi of these and other essential processes induces expression of detoxification and innate immune effectors, even in the absence of toxins or pathogens. Disruption of core processes in non-neuronal tissues was sufficient to stimulate aversion behavior, revealing a neuroendocrine axis of control that additionally required serotonergic and Jnk kinase signaling pathways. We propose that surveillance pathways overseeing core cellular activities allow animals to detect invading pathogens that deploy toxins and virulence factors to undermine vital host functions. Variation in cellular surveillance and endocrine pathways controlling behavior, detoxification, and immunity selected by past toxin or microbial interactions could underlie aberrant responses to foods, medicines, and microbes. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Cell Res
                Cell Res
                Cell Research
                Nature Publishing Group
                1001-0602
                1748-7838
                November 2016
                21 October 2016
                1 November 2016
                : 26
                : 11
                : 1182-1196
                Affiliations
                [1 ]State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871, China
                Author notes
                Article
                cr2016118
                10.1038/cr.2016.118
                5099867
                27767096
                d5842e87-35df-41a7-a02b-5b4bae0628ff
                Copyright © 2016 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

                This license allows readers to copy, distribute and transmit the Contributionas long as it attributed back to the author. Readers are permitted to alter, transform or build upon the Contribution as long as the resulting work is then distributed under this is a similar license. Readers are not permitted to use the Contribution for commercial purposes. Please read the full license for further details at - http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 07 September 2016
                : 18 September 2016
                : 19 September 2016
                Categories
                Original Article

                Cell biology
                mitochondria,unfolded protein response,cell non-autonomous
                Cell biology
                mitochondria, unfolded protein response, cell non-autonomous

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