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      Mitonuclear protein imbalance as a conserved longevity mechanism

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          Abstract

          Longevity is regulated by a network of intimately linked metabolic systems. We used a combination of mouse population genetics and RNAi in C. elegans to identify mitochondrial ribosomal protein S5 ( Mrps5) and other mitochondrial ribosomal proteins (MRPs) as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response (UPR mt). Specific antibiotics targeting mitochondrial translation and ethidium bromide, which impairs mitochondrial DNA transcription, pharmacologically mimic mrp knockdown and extend lifespan by inducing mitonuclear protein imbalance, also in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, UPR mt and lifespan extention in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionary conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to UPR mt, an overarching longevity pathway across multiple species.

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          Most cited references 50

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          Open source clustering software.

          We have implemented k-means clustering, hierarchical clustering and self-organizing maps in a single multipurpose open-source library of C routines, callable from other C and C++ programs. Using this library, we have created an improved version of Michael Eisen's well-known Cluster program for Windows, Mac OS X and Linux/Unix. In addition, we generated a Python and a Perl interface to the C Clustering Library, thereby combining the flexibility of a scripting language with the speed of C. The C Clustering Library and the corresponding Python C extension module Pycluster were released under the Python License, while the Perl module Algorithm::Cluster was released under the Artistic License. The GUI code Cluster 3.0 for Windows, Macintosh and Linux/Unix, as well as the corresponding command-line program, were released under the same license as the original Cluster code. The complete source code is available at http://bonsai.ims.u-tokyo.ac.jp/mdehoon/software/cluster. Alternatively, Algorithm::Cluster can be downloaded from CPAN, while Pycluster is also available as part of the Biopython distribution.
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            Sequence and organization of the human mitochondrial genome.

            The complete sequence of the 16,569-base pair human mitochondrial genome is presented. The genes for the 12S and 16S rRNAs, 22 tRNAs, cytochrome c oxidase subunits I, II and III, ATPase subunit 6, cytochrome b and eight other predicted protein coding genes have been located. The sequence shows extreme economy in that the genes have none or only a few noncoding bases between them, and in many cases the termination codons are not coded in the DNA but are created post-transcriptionally by polyadenylation of the mRNAs.
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              Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

              Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                6 May 2013
                22 May 2013
                22 November 2013
                : 497
                : 7450
                : 451-457
                Affiliations
                [1 ]Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
                [2 ]BioEM Facility, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
                [3 ]Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
                [4 ]Department of Anatomy and Neurobiology and Center for Integrative and Translational Genomics, Memphis, TN, USA
                Author notes
                Correspondence and requests for materials should be addressed to J.A. ( admin.auwerx@ 123456epfl.ch )
                [*‡]

                These authors contributed equally to this work

                Article
                NIHMS468357
                10.1038/nature12188
                3663447
                23698443

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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