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      C. elegans miro-1 Mutation Reduces the Amount of Mitochondria and Extends Life Span

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          Abstract

          Mitochondria play a critical role in aging, however, the underlying mechanism is not well understood. We found that a mutation disrupting the C. elegans homolog of Miro GTPase ( miro-1) extends life span. This phenotype requires simultaneous loss of miro-1 from multiple tissues including muscles and neurons, and is dependent on daf-16/FOXO. Notably, the amount of mitochondria in the miro-1 mutant is reduced to approximately 50% of the wild-type. Despite this reduction, oxygen consumption is only weakly reduced, suggesting that mitochondria of miro-1 mutants are more active than wild-type mitochondria. The ROS damage is slightly reduced and the mitochondrial unfolded protein response pathway is weakly activated in miro-1 mutants. Unlike previously described long-lived mitochondrial electron transport chain mutants, miro-1 mutants have normal growth rate. These results suggest that the reduction in the amount of mitochondria can affect the life span of an organism through activation of stress pathways.

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          Most cited references35

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          Regulation of mitochondrial biogenesis.

          Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer's disease. PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1alpha itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.
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            Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library.

            The recently completed Caenorhabditis elegans genome sequence allows application of high-throughput (HT) approaches for phenotypic analyses using RNA interference (RNAi). As large phenotypic data sets become available, "phenoclustering" strategies can be used to begin understanding the complex molecular networks involved in development and other biological processes. The current HT-RNAi resources represent a great asset for phenotypic profiling but are limited by lack of flexibility. For instance, existing resources do not take advantage of the latest improvements in RNAi technology, such as inducible hairpin RNAi. Here we show that a C. elegans ORFeome resource, generated with the Gateway cloning system, can be used as a starting point to generate alternative HT-RNAi resources with enhanced flexibility. The versatility inherent to the Gateway system suggests that additional HT-RNAi libraries can now be readily generated to perform gene knockdowns under various conditions, increasing the possibilities for phenome mapping in C. elegans.
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              Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

              Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 April 2016
                2016
                : 11
                : 4
                : e0153233
                Affiliations
                [1 ]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
                [2 ]Science Division, Yale-NUS College, Singapore, Singapore
                Brown University/Harvard, UNITED STATES
                Author notes

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

                Conceived and designed the experiments: YS LFN NPWL TH JG TI. Performed the experiments: YS LFN NPWL TI. Analyzed the data: YS LFN NPWL TH JG TI. Contributed reagents/materials/analysis tools: YS LFN NPWL TH JG TI. Wrote the paper: YS LFN TH JG TI.

                Article
                PONE-D-16-07739
                10.1371/journal.pone.0153233
                4827821
                27064409
                c487ade1-8e28-4f1a-8152-6c7edb8942e5
                © 2016 Shen 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
                : 26 February 2016
                : 16 March 2016
                Page count
                Figures: 5, Tables: 0, Pages: 17
                Funding
                Funded by: Singapore Ministry of Education Academic Research Fund
                Award Recipient :
                Funded by: Singapore Ministry of Education Academic Research Fund
                Award ID: MOE2015-T2-1-106
                Award Recipient :
                This work was supported by Singapore Ministry of Education Academic Research Fund: T1-2012-Bridging-04; Singapore Ministry of Education Academic Research Fund: MOE2015-T2-1-106; and Singapore Ministry of Education Academic Research Fund: MOE2014-T2-2-120. 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
                Biochemistry
                Bioenergetics
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Energy-Producing Organelles
                Mitochondria
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Caenorhabditis Elegans
                Biology and Life Sciences
                Organisms
                Animals
                Invertebrates
                Nematoda
                Caenorhabditis
                Caenorhabditis Elegans
                Biology and life sciences
                Genetics
                Epigenetics
                RNA interference
                Biology and life sciences
                Genetics
                Gene expression
                RNA interference
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                Genetics
                Genetic interference
                RNA interference
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                Biochemistry
                Nucleic acids
                RNA
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                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
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                Physiology
                Physiological Processes
                Respiration
                Oxygen Consumption
                Medicine and Health Sciences
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                Physiological Processes
                Respiration
                Oxygen Consumption
                Research and Analysis Methods
                Imaging Techniques
                Fluorescence Imaging
                Biology and life sciences
                Genetics
                DNA
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                Mitochondrial DNA
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                Forms of DNA
                Mitochondrial DNA
                Biology and Life Sciences
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                Oxidative Damage
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                All relevant data are within the paper and its Supporting Information files.

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