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      RNAi of Complex I and V of the electron transport chain in glutamate neurons extends life span, increases sleep, and decreases locomotor activity in Drosophila melanogaster

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          Abstract

          RNAi targeting the electron transport chain has been proven to prolong life span in many different species, and experiments specifically with Drosophila melanogaster and Caenorhabditis elegans have shown a distinct role for neurons. To determine which subset of neurons is implicated in this life span extension, we used the GAL4/UAS system to activate RNAi against genes of Complex I and Complex V. We found life span extension of 18–24% with two glutamate neuron ( D42 and VGlut) GAL4 lines. We used the GAL80 system to determine if the overlapping set of glutamate neurons in these two GAL4 lines imparts the life span extension. Limiting GAL4 activity to non- VGlut glutamate neurons in the D42 background failed to extend life span, suggesting that glutamate neurons have an important role in aging. Interestingly, RNAi of the electron transport chain in D42 glutamate neurons also caused an increase in daytime and nighttime sleep and a decrease in nighttime locomotor activity. Changes to sleep patterns and prolonged life span were not accompanied by any changes in female fertility or response to starvation. Our findings demonstrate that a small subset of neurons can control life span, and further studies can look into the contributions made by glutamate neurons.

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          Most cited references40

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          Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

          During aging, the cellular milieu of the brain exhibits tell-tale signs of compromised bioenergetics, impaired adaptive neuroplasticity and resilience, aberrant neuronal network activity, dysregulation of neuronal Ca 2+ homeostasis, the accrual of oxidatively modified molecules and organelles, and inflammation. These alterations render the aging brain vulnerable to Alzheimer’s and Parkinson’s diseases and stroke. Emerging findings are revealing mechanisms by which sedentary overindulgent lifestyles accelerate brain aging, whereas lifestyles that include intermittent bioenergetic challenges (exercise, fasting, and intellectual challenges) foster healthy brain aging. Here we provide an overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health.
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            A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila.

            Forward genetic screens in model organisms have provided important insights into numerous aspects of development, physiology and pathology. With the availability of complete genome sequences and the introduction of RNA-mediated gene interference (RNAi), systematic reverse genetic screens are now also possible. Until now, such genome-wide RNAi screens have mostly been restricted to cultured cells and ubiquitous gene inactivation in Caenorhabditis elegans. This powerful approach has not yet been applied in a tissue-specific manner. Here we report the generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism. Our RNAi transgenes consist of short gene fragments cloned as inverted repeats and expressed using the binary GAL4/UAS system. We generated 22,270 transgenic lines, covering 88% of the predicted protein-coding genes in the Drosophila genome. Molecular and phenotypic assays indicate that the majority of these transgenes are functional. Our transgenic RNAi library thus opens up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophila lifespan.
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              Mitohormesis.

              For many years, mitochondria were viewed as semiautonomous organelles, required only for cellular energetics. This view has been largely supplanted by the concept that mitochondria are fully integrated into the cell and that mitochondrial stresses rapidly activate cytosolic signaling pathways that ultimately alter nuclear gene expression. Remarkably, this coordinated response to mild mitochondrial stress appears to leave the cell less susceptible to subsequent perturbations. This response, termed mitohormesis, is being rapidly dissected in many model organisms. A fuller understanding of mitohormesis promises to provide insight into our susceptibility for disease and potentially provide a unifying hypothesis for why we age. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Writing – original draft
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 June 2023
                2023
                : 18
                : 6
                : e0286828
                Affiliations
                [001] Department of Biology, Eastern Mennonite University, Harrisonburg, VA, United States of America
                Biomedical Sciences Research Center Alexander Fleming, GREECE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0001-7873-1194
                https://orcid.org/0000-0001-5432-3524
                Article
                PONE-D-22-34511
                10.1371/journal.pone.0286828
                10270625
                f74a9b88-664b-41f4-bf2c-e5b1dd8a1d07
                © 2023 Landis et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 December 2022
                : 24 May 2023
                Page count
                Figures: 4, Tables: 1, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100011439, Virginia Academy of Science;
                Award ID: Small Project Research Grant
                Award Recipient :
                J.M.C. is supported by a Small Project Research Grant from the Virginia Academy of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”
                Categories
                Research Article
                Biology and life sciences
                Genetics
                Epigenetics
                RNA interference
                Biology and life sciences
                Genetics
                Gene expression
                RNA interference
                Biology and life sciences
                Genetics
                Genetic interference
                RNA interference
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                RNA interference
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
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                Neuroscience
                Cellular Neuroscience
                Neurons
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Sleep
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Glutamate
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                Neuroscience
                Neurochemistry
                Neurotransmitters
                Glutamate
                Biology and Life Sciences
                Biochemistry
                Bioenergetics
                Electron Transport Chain
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                Bioenergetics
                Energy-Producing Organelles
                Mitochondria
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                Cell Biology
                Cellular Structures and Organelles
                Energy-Producing Organelles
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                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Motor Neurons
                Biology and Life Sciences
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                Research and Analysis Methods
                Animal Studies
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                Drosophila Melanogaster
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                Biology and Life Sciences
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