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  • 1
    Publication Date: 2011-10-08
    Description: Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-alpha and PGC1alpha (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189541/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189541/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McDermott-Roe, Chris -- Ye, Junmei -- Ahmed, Rizwan -- Sun, Xi-Ming -- Serafin, Anna -- Ware, James -- Bottolo, Leonardo -- Muckett, Phil -- Canas, Xavier -- Zhang, Jisheng -- Rowe, Glenn C -- Buchan, Rachel -- Lu, Han -- Braithwaite, Adam -- Mancini, Massimiliano -- Hauton, David -- Marti, Ramon -- Garcia-Arumi, Elena -- Hubner, Norbert -- Jacob, Howard -- Serikawa, Tadao -- Zidek, Vaclav -- Papousek, Frantisek -- Kolar, Frantisek -- Cardona, Maria -- Ruiz-Meana, Marisol -- Garcia-Dorado, David -- Comella, Joan X -- Felkin, Leanne E -- Barton, Paul J R -- Arany, Zoltan -- Pravenec, Michal -- Petretto, Enrico -- Sanchis, Daniel -- Cook, Stuart A -- 087183/Wellcome Trust/United Kingdom -- MC_U120085815/Medical Research Council/United Kingdom -- MC_U120097112/Medical Research Council/United Kingdom -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Oct 5;478(7367):114-8. doi: 10.1038/nature10490.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21979051" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Body Weight/genetics ; Cardiomegaly/*enzymology/genetics/*pathology/physiopathology ; Cell Respiration ; Chromosomes, Mammalian/genetics ; Crosses, Genetic ; Endodeoxyribonucleases/deficiency/genetics/*metabolism ; Female ; Gene Expression Regulation ; Genes, Mitochondrial/genetics ; Hypertrophy, Left Ventricular/enzymology/genetics/pathology/physiopathology ; Lipid Metabolism ; Male ; Mitochondria/genetics/*metabolism/pathology ; Organ Size/genetics ; Quantitative Trait Loci/genetics ; RNA-Binding Proteins/metabolism ; Rats ; Rats, Inbred Strains ; Reactive Oxygen Species/metabolism ; Receptors, Estrogen/metabolism ; Transcription Factors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-12-18
    Description: During endocytosis, energy is invested to narrow the necks of cargo-containing plasma membrane invaginations to radii at which the opposing segments spontaneously coalesce, thereby leading to the detachment by scission of endocytic uptake carriers. In the clathrin pathway, dynamin uses mechanical energy from GTP hydrolysis to this effect, assisted by the BIN/amphiphysin/Rvs (BAR) domain-containing protein endophilin. Clathrin-independent endocytic events are often less reliant on dynamin, and whether in these cases BAR domain proteins such as endophilin contribute to scission has remained unexplored. Here we show, in human and other mammalian cell lines, that endophilin-A2 (endoA2) specifically and functionally associates with very early uptake structures that are induced by the bacterial Shiga and cholera toxins, which are both clathrin-independent endocytic cargoes. In controlled in vitro systems, endoA2 reshapes membranes before scission. Furthermore, we demonstrate that endoA2, dynamin and actin contribute in parallel to the scission of Shiga-toxin-induced tubules. Our results establish a novel function of endoA2 in clathrin-independent endocytosis. They document that distinct scission factors operate in an additive manner, and predict that specificity within a given uptake process arises from defined combinations of universal modules. Our findings highlight a previously unnoticed link between membrane scaffolding by endoA2 and pulling-force-driven dynamic scission.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342003/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342003/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Renard, Henri-Francois -- Simunovic, Mijo -- Lemiere, Joel -- Boucrot, Emmanuel -- Garcia-Castillo, Maria Daniela -- Arumugam, Senthil -- Chambon, Valerie -- Lamaze, Christophe -- Wunder, Christian -- Kenworthy, Anne K -- Schmidt, Anne A -- McMahon, Harvey T -- Sykes, Cecile -- Bassereau, Patricia -- Johannes, Ludger -- R01 GM106720/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jan 22;517(7535):493-6. doi: 10.1038/nature14064. Epub 2014 Dec 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institut Curie - Centre de Recherche, Endocytic Trafficking and Therapeutic Delivery group, 26 rue d'Ulm, 75248 Paris Cedex 05, France [2] CNRS UMR3666, 75005 Paris, France [3] U1143 INSERM, 75005 Paris, France. ; 1] Institut Curie - Centre de Recherche, Membrane and Cell Functions group, CNRS UMR 168, Physico-Chimie Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France [2] The University of Chicago, Department of Chemistry, 5735 S Ellis Ave, Chicago, Ilinois 60637, USA. ; 1] Institut Curie - Centre de Recherche, Biomimetism of Cell Movement group, CNRS UMR 168, Physico-Chimie Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France [2] Universite Paris Diderot, Sorbonne Paris Cite, 75205 Paris, France. ; Institute of Structural and Molecular Biology, University College London &Birkbeck College, London WC1E 6BT, UK. ; 1] CNRS UMR3666, 75005 Paris, France [2] U1143 INSERM, 75005 Paris, France [3] Institut Curie - Centre de Recherche, Membrane Dynamics and Mechanics of Intracellular Signaling group, 26 rue d'Ulm, 75248 Paris Cedex 05, France. ; Vanderbilt School of Medicine, Department of Molecular Physiology and Biophysics, 718 Light Hall, Nashville, Tennessee 37232, USA. ; CNRS, UMR7592, Institut Jacques Monod, Universite Paris Diderot, Sorbonne Paris Cite, 15 rue Helene Brion, 75205 Paris Cedex 13, France. ; Medical Research Council, Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; Institut Curie - Centre de Recherche, Biomimetism of Cell Movement group, CNRS UMR 168, Physico-Chimie Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France. ; Institut Curie - Centre de Recherche, Membrane and Cell Functions group, CNRS UMR 168, Physico-Chimie Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517096" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Acyltransferases/*metabolism ; Animals ; Cell Line ; Cell Membrane/*metabolism ; Cholera Toxin/metabolism ; Clathrin ; Dynamins/metabolism ; *Endocytosis ; Humans ; Rats ; Shiga Toxin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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