title: Lysosomal Dysfunction Caused by Cellular Accumulation of Silica Nanoparticles.
abstract: Nanoparticles (NPs) are widely used as components of drugs or cosmetics and hold great promise for biomedicine, yet their effects on cell physiology remain poorly understood. Here we demonstrate that clathrin-independent dynamin 2-mediated caveolar uptake of surface-functionalized silica nanoparticles (SiNPs) impairs cell viability due to lysosomal dysfunction. We show that internalized SiNPs accumulate in lysosomes resulting in inhibition of autophagy-mediated protein turnover and impaired degradation of internalized epidermal growth factor, whereas endosomal recycling proceeds unperturbed. This phenotype is caused by perturbed delivery of cargo via autophagosomes and late endosomes to SiNP-filled cathepsin B/L-containing lysosomes rather than elevated lysosomal pH or altered mTOR activity. Given the importance of autophagy and lysosomal protein degradation for cellular proteostasis and clearance of aggregated proteins, these results raise the question of beneficial use of NPs in biomedicine and beyond.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Schütz
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Lopez-Hernandez
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Puchkov
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany,; Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jabs
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nordmeyer
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Schmudde
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Rühl
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Graf
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany,; Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany. Electronic address: haucke@fmp-berlin.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
mesh_terms: D004705:Endocytosis; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D053758:Nanoparticles; D012822:Silicon Dioxide / Q000378:metabolism*
chemical_list: D012822:Silicon Dioxide
keywords: autophagy; caveolae; endocytosis; endosome; lysosome; silica nanoparticles