Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification

Wim Dejonghe, Sabine Kuenen, Evelien Mylle, Mina Vasileva, Olivier Keech, Corrado Viotti, Jef Swerts, Matyáš 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-Mária Szatmári, Mateusz Majda, Gary Baisa, Sebastian York Bednarek, Stéphanie Robert, Dominique Audenaert, Christa Testerink, Teun Munnik, Daniël Van Damme, Ingo Heilmann, Karin Schumacher, Johan Winne, Jiří Friml, Patrik Verstreken and Eugenia Russinova ()
Additional contact information
Wim Dejonghe: Department of Plant Systems Biology
Sabine Kuenen: VIB Center for the Biology of Disease, Laboratory of Neuronal Communication
Evelien Mylle: Department of Plant Systems Biology
Mina Vasileva: Institute of Science and Technology Austria
Olivier Keech: Umeå Plant Science Centre, Umeå University
Corrado Viotti: Institute of Biochemistry and Biology, University of Potsdam
Jef Swerts: VIB Center for the Biology of Disease, Laboratory of Neuronal Communication
Matyáš Fendrych: Institute of Science and Technology Austria
Fausto Andres Ortiz-Morea: Department of Plant Systems Biology
Kiril Mishev: Department of Plant Systems Biology
Simon Delang: Developmental Biology of Plants, Centre for Organismal Studies, Heidelberg University
Stefan Scholl: Developmental Biology of Plants, Centre for Organismal Studies, Heidelberg University
Xavier Zarza: Swammerdam Institute for Life Sciences, University of Amsterdam
Mareike Heilmann: Institute for Biochemistry and Biotechnology, Martin-Luther-University
Jiorgos Kourelis: Swammerdam Institute for Life Sciences, University of Amsterdam
Jaroslaw Kasprowicz: VIB Center for the Biology of Disease, Laboratory of Neuronal Communication
Le Son Long Nguyen: Compound Screening Facility
Andrzej Drozdzecki: Compound Screening Facility
Isabelle Van Houtte: Department of Plant Systems Biology
Anna-Mária Szatmári: Department of Plant Systems Biology
Mateusz Majda: Umeå Plant Science Centre, Swedish University of Agricultural Sciences
Gary Baisa: University of Wisconsin-Madison
Sebastian York Bednarek: University of Wisconsin-Madison
Stéphanie Robert: Umeå Plant Science Centre, Swedish University of Agricultural Sciences
Dominique Audenaert: Compound Screening Facility
Christa Testerink: Swammerdam Institute for Life Sciences, University of Amsterdam
Teun Munnik: Swammerdam Institute for Life Sciences, University of Amsterdam
Daniël Van Damme: Department of Plant Systems Biology
Ingo Heilmann: Institute for Biochemistry and Biotechnology, Martin-Luther-University
Karin Schumacher: Developmental Biology of Plants, Centre for Organismal Studies, Heidelberg University
Johan Winne: Laboratory for Organic Synthesis, Ghent University
Jiří Friml: Institute of Science and Technology Austria
Patrik Verstreken: VIB Center for the Biology of Disease, Laboratory of Neuronal Communication
Eugenia Russinova: Department of Plant Systems Biology

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11710

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