Wim Dejonghe, Sabine Kuenen, Evelien Mylle, Mina Vasileva, Olivier Keech, Corrado Viotti, Jef Swerts, Matyas Fendrych, Fausto Andres Ortiz-Morea, Kiril Mishev, Simon Delang, Stefan Scholl, Xavier Zarza, Mareike Heilmann, Jiorgos Kourelis, Jaroslaw Kasprowicz, Le Son Long Nguyen, Andrzej Drozdzecki, Isabelle Van Houtte, Anna-Maria Szatmari, Mateusz Majda, Gary Baisa, Sebastian York Bednarek, Stephanie Robert, Dominique Audenaert, Christa Testerink, Teun Munnik, Daniel Van Damme, Ingo Heilmann, Karin Schumacher, Johan Winne, Jiri Friml, Patrik Verstreken, Eugenia Russinova
- 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 ofATP 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.…
MetadatenAuthor details: | Wim Dejonghe, Sabine Kuenen, Evelien Mylle, Mina Vasileva, Olivier Keech, Corrado ViottiORCiD, Jef Swerts, Matyas Fendrych, Fausto Andres Ortiz-Morea, Kiril Mishev, Simon Delang, Stefan Scholl, Xavier Zarza, Mareike Heilmann, Jiorgos Kourelis, Jaroslaw Kasprowicz, Le Son Long Nguyen, Andrzej Drozdzecki, Isabelle Van Houtte, Anna-Maria Szatmari, Mateusz Majda, Gary Baisa, Sebastian York Bednarek, Stephanie Robert, Dominique Audenaert, Christa Testerink, Teun Munnik, Daniel Van Damme, Ingo Heilmann, Karin Schumacher, Johan Winne, Jiri Friml, Patrik Verstreken, Eugenia Russinova |
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DOI: | https://doi.org/10.1038/ncomms11710 |
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ISSN: | 2041-1723 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/27271794 |
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Title of parent work (English): | Nature Communications |
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Publisher: | Nature Publ. Group |
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Place of publishing: | London |
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Publication type: | Article |
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Language: | English |
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Year of first publication: | 2016 |
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Publication year: | 2016 |
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Release date: | 2020/03/22 |
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Volume: | 7 |
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Number of pages: | 12 |
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First page: | 1959 |
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Last Page: | 1968 |
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Funding institution: | Agency for Innovation by Science and Technology; Research fund KU Leuven (GOA); Methusalem grant of the Flemish government; VIB; Netherlands Organisation for Scientific Research (NWO) [846.11.002, 867.15.020]; European Research Council [ERC-2011-StG-20101109 PSDP]; European Research Council (ERC) Starting Grant [260678]; Research Foundation-Flanders [G.0747.09, G094011, G095511]; Hercules Foundation; Interuniversity Attraction Poles Poles Program; Swedish VetenskapsRadet; Foundation-Flanders (FWO) |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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Peer review: | Referiert |
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