title: Loss of PINK1 impairs stress-induced autophagy and cell survival.
abstract: The mitochondrial kinase PINK1 and the ubiquitin ligase Parkin are participating in quality control after CCCP- or ROS-induced mitochondrial damage, and their dysfunction is associated with the development and progression of Parkinson's disease. Furthermore, PINK1 expression is also induced by starvation indicating an additional role for PINK1 in stress response. Therefore, the effects of PINK1 deficiency on the autophago-lysosomal pathway during stress were investigated. Under trophic deprivation SH-SY5Y cells with stable PINK1 knockdown showed downregulation of key autophagic genes, including Beclin, LC3 and LAMP-2. In good agreement, protein levels of LC3-II and LAMP-2 but not of LAMP-1 were reduced in different cell model systems with PINK1 knockdown or knockout after addition of different stressors. This downregulation of autophagic factors caused increased apoptosis, which could be rescued by overexpression of LC3 or PINK1. Taken together, the PINK1-mediated reduction of autophagic key factors during stress resulted in increased cell death, thus defining an additional pathway that could contribute to the progression of Parkinson's disease in patients with PINK1 mutations.
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Dajana
authors.initials: D
authors.lastname: Parganlija
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Domínguez-Bautista
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Hetzel
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.affiliation: Molecular Bioenergetics Group, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Marthe A
authors.initials: MA
authors.lastname: Chimi
authors.affiliation: Molecular Bioenergetics Group, Goethe University Medical School, Frankfurt/Main, Germany; Clinic of Anesthesiology, Intensive-Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.affiliation: Kinematic Cell Research Group, Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt: Macromolecular Complexes, Goethe University, Frankfurt/Main, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Mai
authors.affiliation: Molecular Bioenergetics Group, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.affiliation: Experimental Neurology, Dept. of Neurology, Goethe University Medical School, Frankfurt/Main, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Jendrach
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D011494:Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D008869:Microtubule-Associated Proteins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C497811:LAMP2 protein, human; C477012:MAP1LC3A protein, human
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