Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification

Dejonghe, Wim, Kuenen, Sabine, Mylle, Evelien, Vasileva, Mina, Keech, Olivier, Viotti, Corrado, Swerts, Jef, Fendrych, Matyáš, Ortiz-Morea, Fausto Andres, Mishev, Kiril, Delang, Simon, Scholl, Stefan, Zarza, Xavier, Heilmann, Mareike, Kourelis, Jiorgos ORCID: https://orcid.org/0000-0002-9007-1333, Kasprowicz, Jaroslaw, Nguyen, Le Son Long, Drozdzecki, Andrzej, van Houtte, Isabelle, Szatmári, Anna Mária, Majda, Mateusz, Baisa, Gary, Bednarek, Sebastian York, Robert, Stéphanie, Audenaert, Dominique, Testerink, Christa, Munnik, Teun, van Damme, Daniël, Heilmann, Ingo, Schumacher, Karin, Winne, Johan, Friml, Jií, Verstreken, Patrik and Russinova, Eugenia (2016) Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification. Nature Communications, 7. ISSN 2041-1723

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Abstract

ATP production requires the establishment of an electrochemical proton gradient across the inner mitochondrial membrane. Mitochondrial uncouplers dissipate this proton gradient and disrupt numerous cellular processes, including vesicular trafficking, mainly through energy depletion. Here we show that Endosidin9 (ES9), a novel mitochondrial uncoupler, is a potent inhibitor of clathrin-mediated endocytosis (CME) in different systems and that ES9 induces inhibition of CME not because of its effect on cellular ATP, but rather due to its protonophore activity that leads to cytoplasm acidification. We show that the known tyrosine kinase inhibitor tyrphostinA23, which is routinely used to block CME, displays similar properties, thus questioning its use as a specific inhibitor of cargo recognition by the AP-2 adaptor complex via tyrosine motif-based endocytosis signals. Furthermore, we show that cytoplasm acidification dramatically affects the dynamics and recruitment of clathrin and associated adaptors, and leads to reduction of phosphatidylinositol 4,5-biphosphate from the plasma membrane.

Item Type: Article
Additional Information: Funding information: This work was supported by the Agency for Innovation by Science and Technology for a pre-doctoral fellowship to W.D.; the Research fund KU Leuven (GOA), a Methusalem grant of the Flemish government and VIB to S.K., J.K. and P.V.; by the Netherlands Organisation for Scientific Research (NWO) for ALW grants 846.11.002 (C.T.) and 867.15.020 (T.M.); the European Research Council (project ERC-2011-StG-20101109 PSDP) (to J.F.); a European Research Council (ERC) Starting Grant (grant 260678) (to P.V.), the Research Foundation-Flanders (grants G.0747.09, G094011 and G095511) (to P.V.), the Hercules Foundation, an Interuniversity Attraction Poles Poles Program, initiated by the Belgian State, Science Policy Office (to P.V.), the Swedish VetenskapsRådet grant to O.K., the Ghent University ‘Bijzonder Onderzoek Fonds’ (BOF) for a predoctoral fellowship to F.A.O.-M., the Research Foundation-Flanders (FWO) to K.M. and E.R.
Uncontrolled Keywords: chemistry(all),biochemistry, genetics and molecular biology(all),physics and astronomy(all) ,/dk/atira/pure/subjectarea/asjc/1600
Faculty \ School: Faculty of Science > The Sainsbury Laboratory
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Depositing User: LivePure Connector
Date Deposited: 07 Dec 2023 01:46
Last Modified: 01 Feb 2024 03:08
URI: https://ueaeprints.uea.ac.uk/id/eprint/93903
DOI: 10.1038/ncomms11710

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