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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 references24

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          Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

          Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
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            Supercomplexes in the respiratory chains of yeast and mammalian mitochondria.

            Around 30-40 years after the first isolation of the five complexes of oxidative phosphorylation from mammalian mitochondria, we present data that fundamentally change the paradigm of how the yeast and mammalian system of oxidative phosphorylation is organized. The complexes are not randomly distributed within the inner mitochondrial membrane, but assemble into supramolecular structures. We show that all cytochrome c oxidase (complex IV) of Saccharomyces cerevisiae is bound to cytochrome c reductase (complex III), which exists in three forms: the free dimer, and two supercomplexes comprising an additional one or two complex IV monomers. The distribution between these forms varies with growth conditions. In mammalian mitochondria, almost all complex I is assembled into supercomplexes comprising complexes I and III and up to four copies of complex IV, which guided us to present a model for a network of respiratory chain complexes: a 'respirasome'. A fraction of total bovine ATP synthase (complex V) was isolated in dimeric form, suggesting that a dimeric state is not limited to S.cerevisiae, but also exists in mammalian mitochondria.
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              Variations in DNA elucidate molecular networks that cause disease.

              Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.
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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
                b3d02cf3-f133-4ea6-a44c-70da7b5f94c8

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