Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification

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.

Kuenen, Sabine (author)
Mylle, Evelien (author)
Vasileva, Mina (author)
Keech, OlivierUmeå universitet,Institutionen för fysiologisk botanik,Umeå Plant Science Centre (UPSC)(Swepub:umu)olke0001 (author)
Viotti, Corrado (author)
Swerts, Jef (author)
Fendrych, Matyas (author)
Ortiz-Morea, Fausto Andres (author)
Mishev, Kiril (author)
Delang, Simon (author)
Scholl, Stefan (author)
Zarza, Xavier (author)
Heilmann, Mareike (author)
Kourelis, Jiorgos (author)
Kasprowicz, Jaroslaw (author)
Nguyen, Le Son Long (author)
Drozdzecki, Andrzej (author)
Van Houtte, Isabelle (author)
Szatmari, Anna-Maria (author)
Majda, MateuszSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology(Swepub:slu)96291 (author)
Baisa, Gary (author)
Bednarek, Sebastian York (author)
Robert, StephanieSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology(Swepub:slu)49889 (author)
Audenaert, Dominique (author)
Testerink, Christa (author)
Munnik, Teun (author)
Van Damme, Daniel (author)
Heilmann, Ingo (author)
Schumacher, Karin (author)
Winne, Johan (author)
Friml, Jiri (author)
Verstreken, Patrik (author)
Russinova, Eugenia (author)
Umeå universitetInstitutionen för fysiologisk botanik (creator_code:org_t)
Sveriges lantbruksuniversitet

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

By the university: Umeå University; Swedish University of Agricultural Sciences

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