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      Loss of Mitochondrial Membrane Potential Triggers the Retrograde Response Extending Yeast Replicative Lifespan

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          Abstract

          In the budding yeast Saccharomyces cerevisiae, loss of mitochondrial DNA (rho 0) can induce the retrograde response under appropriate conditions, resulting in increased replicative lifespan (RLS). Although the retrograde pathway has been extensively elaborated, the nature of the mitochondrial signal triggering this response has not been clear. Mitochondrial membrane potential (MMP) was severely reduced in rho 0 compared to rho + cells, and RLS was concomitantly extended. To examine the role of MMP in the retrograde response, MMP was increased in the rho 0 strain by introducing a mutation in the ATP1 gene, and it was decreased in rho + cells by deletion of COX4. The ATP1-111 mutation in rho 0 cells partially restored the MMP and reduced mean RLS to that of rho + cells. COX4 deletion decreased MMP in rho + cells to a value intermediate between rho + and rho 0 cells and similarly increased RLS. The increase in expression of CIT2, the diagnostic gene for the retrograde response, seen in rho 0 cells, was substantially suppressed in the presence of the ATP1-111 mutation. In contrast, CIT2 expression increased in rho + cells on deletion of COX4. Activation of the retrograde response results in the translocation of the transcription factor Rtg3 from the cytoplasm to the nucleus. Rtg3–GFP translocation to the nucleus was directly observed in rho 0 and rho + cox4Δ cells, but it was blunted in rho 0 cells with the ATP1-111 mutation. We conclude that a decrease in MMP is the signal that initiates the retrograde response and leads to increased RLS.

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          Most cited references 39

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          Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients.

           M Kaeberlein (2005)
          Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.
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            An ER-mitochondria tethering complex revealed by a synthetic biology screen.

            Communication between organelles is an important feature of all eukaryotic cells. To uncover components involved in mitochondria/endoplasmic reticulum (ER) junctions, we screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. The tethering complex was composed of proteins resident of both ER and mitochondria. With the use of genome-wide mapping of genetic interactions, we showed that the components of the tethering complex were functionally connected to phospholipid biosynthesis and calcium-signaling genes. In mutant cells, phospholipid biosynthesis was impaired. The tethering complex localized to discrete foci, suggesting that discrete sites of close apposition between ER and mitochondria facilitate interorganelle calcium and phospholipid exchange.
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              Mitochondrial retrograde signaling.

              Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus under normal and pathophysiological conditions. The best understood of such pathways is retrograde signaling in the budding yeast Saccharomyces cerevisiae. It involves multiple factors that sense and transmit mitochondrial signals to effect changes in nuclear gene expression; these changes lead to a reconfiguration of metabolism to accommodate cells to defects in mitochondria. Analysis of regulatory factors has provided us with a mechanistic view of regulation of retrograde signaling. Here we review advances in the yeast retrograde signaling pathway and highlight its regulatory factors and regulatory mechanisms, its physiological functions, and its connection to nutrient sensing, TOR signaling, and aging.
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                Author and article information

                Journal
                Front Genet
                Front. Gene.
                Frontiers in Genetics
                Frontiers Research Foundation
                1664-8021
                10 January 2012
                2011
                : 2
                Affiliations
                1Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center New Orleans, LA, USA
                Author notes

                Edited by: Yidong Bai, University of Texas Health Science Center at San Antonio, USA

                Reviewed by: Lokendra Kumar Sharma, University of Texas Health Science Center at San Antonio, USA; Xin Jie Chen, SUNY Upstate Medical University, USA

                *Correspondence: S. Michal Jazwinski, Department of Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-12, New Orleans, LA 70112, USA. e-mail: sjazwins@ 123456tulane.edu

                Present address: Jose F. Rodriguez-Quiñones, Department of Chemistry, College of Sciences, Pontifical Catholic University of Puerto Rico, Ponce, PR, USA.

                This article was submitted to Frontiers in Genetics of Aging, a specialty of Frontiers in Genetics.

                Article
                10.3389/fgene.2011.00102
                3266616
                22303396
                Copyright © 2012 Miceli, Jiang, Tiwari, Rodriguez-Quiñones and Jazwinski.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 42, Pages: 11, Words: 7072
                Categories
                Genetics
                Original Research

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