title: Perfluorooctane Sulfonate Induces Autophagy-Dependent Apoptosis through Spinster 1-Mediated lysosomal-Mitochondrial Axis and Impaired Mitophagy.
abstract: Lysosomal membrane permeabilization (LMP) and subsequently impaired autophagosome degradation was induced in HepG2 cells after treatment with perfluorooctane sulfonate (PFOS) for 24 h in our previous studies. We found that treatment of HepG2 cells with PFOS-induced autophagosome formation at earlier stage (6 h) of treatment in this study. The autophagosome formation inhibitor 3-methyladenine (3-MA) was able to relieve PFOS-induced LMP and release of cathepsin D in HepG2 cells. Knockdown of Spinster 1, a lysosomal membrane permease, attenuated PFOS-induced LMP in HepG2 cells. We proposed that Spinster 1 might work as a specific molecule that linked autophagy with LMP. PFOS-induced collapse of mitochondrial transmembrane potential was cathepsin D and autophagy dependent. Addition of 3-MA relieved PFOS-induced apoptosis, which was evidenced by Hoechst assay, AV/PI staining and caspase-3 activity assay. Inhibition of autophagosome formation by Atg5 siRNA attenuated PFOS-induced apoptosis. Treatment of HepG2 cells with PFOS for 24 h impaired mitophagy, as evidenced by an increase of cells with giant mitochondria and impairment of colocalization of PINK1 with light chain 3. In summary, we report that PFOS induces autophagy-dependent apoptosis in HepG2 cells through the lysosomal-mitochondrial axis and impairment of mitophagy, suggesting that autophagy is a primary target for PFOS toxicity. These findings provide new mechanistic insights into PFOS-induced hepatotoxicity.
authors.affiliation: *Department of Biochemistry and Molecular Biology Department of Occupational and Environmental Health, Dalian Medical University, 9 W Lushun South Road, Dalian 116044, People's Republic of China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yao
authors.affiliation: *Department of Biochemistry and Molecular Biology.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, 9 W Lushun South Road, Dalian 116044, People's Republic of China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, 9 W Lushun South Road, Dalian 116044, People's Republic of China.
authors.forename: Xiance
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, 9 W Lushun South Road, Dalian 116044, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.affiliation: *Department of Biochemistry and Molecular Biology.
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, 9 W Lushun South Road, Dalian 116044, People's Republic of China.
authors.forename: Liping
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, 9 W Lushun South Road, Dalian 116044, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: *Department of Biochemistry and Molecular Biology yufang_ma@hotmail.com.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Ma
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D005466:Fluorocarbons / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D063306:Mitophagy / Q000187:drug effects*; D034622:RNA Interference
chemical_list: D017738:Alkanesulfonic Acids; D005466:Fluorocarbons; C076994:perfluorooctane sulfonic acid
keywords: Spinster 1; apoptosis; autophagy; lysosomal-mitochondrial axis; mitophagy; perfluorooctane sulfonate