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Nat Commun. 2016 Jun 8;7:11710. doi: 10.1038/ncomms11710.

Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification.

Author information

1
Department of Plant Systems Biology, VIB, 9052 Gent, Belgium.
2
Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium.
3
VIB Center for the Biology of Disease, Laboratory of Neuronal Communication, 3000 Leuven, Belgium.
4
Department for Human Genetics, and Leuven Institute for Neurodegenerative Diseases, KU Leuven, 3000 Leuven, Belgium.
5
Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria.
6
Department of Plant Physiology, Umeå Plant Science Centre, Umeå University, 90187 Umeå, Sweden.
7
Department of Plant Physiology, Institute of Biochemistry and Biology, University of Potsdam, 14476 Potsdam, Germany.
8
Developmental Biology of Plants, Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany.
9
Department of Plant Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, 1090 GE Amsterdam, The Netherlands.
10
Department of Cellular Biochemistry, Institute for Biochemistry and Biotechnology, Martin-Luther-University, 06120 Halle, Germany.
11
Compound Screening Facility, VIB, 9052 Ghent, Belgium.
12
Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, 90183 Umeå, Sweden.
13
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
14
Laboratory for Organic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, 9000 Gent, Belgium.

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.

PMID:
27271794
PMCID:
PMC4899852
DOI:
10.1038/ncomms11710
[Indexed for MEDLINE]
Free PMC Article

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